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Review Metabolic N-Dealkylation and N-Oxidation as Elucidators of the Role of Alkylamino Moieties in Acting at Various Receptors

Babiker M. EH-Haj

Department of Pharmaceutical Sciences, College of and Health Sciences, University of Science and Technology of Fujairah, Emirate of Fujairah, Fujairah 2022, United Arab Emirates; [email protected]; Tel.: +971-567-204-338

Abstract: Metabolic reactions that occur at alkylamino moieties may provide insight into the roles of these moieties when they are parts of molecules that act at different receptors. N-dealkylation of N,N-dialkylamino moieties has been associated with retaining, attenuation or loss of pharmacologic activities of metabolites compared to their parent drugs. Further, N-dealkylation has resulted in clinically used drugs, of , change of selectivity, and providing potential for developing fully-fledged drugs. While both secondary and tertiary alkylamino moieties (open chain aliphatic or heterocyclic) are metabolized by CYP450 oxidative N-dealkylation, only tertiary alkylamino moieties are subject to metabolic N-oxidation by Flavin-containing monooxyge- nase (FMO) to give N-oxide products. In this review, two aspects will be examined after surveying the of representative alkylamino-moieties-containing drugs that act at various receptors (i) the pharmacologic activities and relevant physicochemical properties (basicity and polarity) of the   metabolites with respect to their parent drugs and (ii) the role of alkylamino moieties on the molecu- lar docking of drugs in receptors. Such information is illuminative in structure-based Citation: EH-Haj, B.M. Metabolic N-Dealkylation and N-Oxidation as considering that fully-fledged metabolite drugs and metabolite prodrugs have been, respectively, Elucidators of the Role of Alkylamino developed from N-desalkyl and N-oxide metabolites. Moieties in Drugs Acting at Various Receptors. Molecules 2021, 26, 1917. Keywords: N-alkylamino moieties; metabolic N-dealkylation; metabolic N-oxidation; pharmacologic https://doi.org/10.3390/ activity; physicochemical properties; N-desalkylamino metabolite drugs; N-oxide metabolite prodrugs molecules26071917

Academic Editor: David Díez Table of Contents Received: 8 March 2021 Accepted: 24 March 2021 Section Topics Pages Published: 29 March 2021 Abstract 1 1. Introduction 3 Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in 2. (NT) Inhibitors 4 published maps and institutional affil- 2.1. - Reuptake Inhibitors 4 iations. 2.1.1. and 4, 5 2.1.2 6 2.1.3 6, 7 Copyright: © 2021 by the author. 2.1.4. 7 Licensee MDPI, Basel, Switzerland. 2.2. Selective Norepinephrine Reuptake Inhibitors 7 This article is an open access article distributed under the terms and 2.2.1 7, 8 conditions of the Creative Commons 2.2.2. 8 Attribution (CC BY) license (https:// 2.3. Selective Serotonin Reuptake Inhibitors 9 creativecommons.org/licenses/by/ 4.0/).

Molecules 2021, 26, 1917. https://doi.org/10.3390/molecules26071917 https://www.mdpi.com/journal/molecules Molecules 2021, 26, 1917 2 of 40

Section Topics Pages 2.3.1. 9 2.3.2. / 9, 10 2.3.3. 10 2.3.4. Fenfluramine 10, 11 , , and 3. 11 N-methyl-D-aspartate (NMDA) Receptor Blockers 3.1. / 11 3.2. 11, 12 3.3. 12 3.4. 12, 13 3.5. 13 3.6. 14 3.7. 14, 15 3.8. 15 4. -1 Receptor Antagonists 16 4.1. 16 4.2. 16, 17 4.3. Prometazine 17 5. -mu-Receptor 17 5.1. / 17, 18 5.2. 18 5.3. Propoxyphene 19 5.4. Meperidine 19 6. -Channel Blockers 20 6.1. 20 6.2. 20 6.3. 21 7. Drugs That Act at Sodiuzm Channels 21 7.1. Local 21 7.1.1 21 8. Drugs That Act at GABAnergic Receptors 22 8.1. 22 9. Muscarinic-Receptor Blockers 22 9.1. / 22, 23 9.2. 23, 10. “If” Channel Blockers 23 10.1. Ivabradine 23,24 11. Drugs That Act as Inhibitors 24 11.1. Sildenafil 24 12. Drugs That Act on Microorganisms 24 12.1. /Hydroxychloroquine 24–26 13. Anticancer Drugs 26 Molecules 2021, 26, 1917 3 of 40

Section Topics Pages 13.1. 26 13.2. Dacarbazine 26, 27 13.3. 27 13.4. Tormifene 27, 28 14. Metabolic N-dealkylation and N-oxidation 28 14.1. Metabolic N-dealkylation 28, 29 14.1.1. Focused N-dealkylation cases 30 14.1.1.1. Loss of Pharmacologic Activity 30 Molecules 2021, 26, x FOR PEER REVIEW 3 of 41 14.1.1.2. Modification of Receptor Inhibition Selectivity 30, 31 14.1.1.3. Activation of Prodrugs 31 14.1.1.4. 1. IntroductionPotential Drug Candidates (Metabolite Drugs) 31 Alkylamino moieties,N-Oxidation either open Of chain aliphatic (secondary or tertiary), or heterocy- 14.2. 32 clic tertiaryTertiary-Alkylamino-Moiety-Containing ones, are common in drug molecules of Drug various pharmacological classes. Their basicity and polarity are essential for drug action. They are found in , an- 15. tihistamines, ,Conclusions local anesthetics, as well as other drug 33 classes. The order of prevalence of the alky groups in alkylamino moieties is methyl > ethyl > isopropyl > 1. Introduction tert-butyl > others. Methyl, ethyl, and isopropyl groups are usually found in drug mole- Alkylaminocules moieties, as tertiary either N,N open-dimethylamino, chain aliphatic N,N-diethylamino, (secondary or or tertiary),N,N-diisopropylamino or hetero- moie- ties, respectively. In the metabolism of drug molecules containing N,N-dimethylamino, cyclic tertiary ones, are common in drug molecules of various pharmacological classes. N,N-diethylamino and N,N-diisopropylamino moieties, the alkyl groups are mostly re- Their basicity and polarity are essential for drug action. They are found in antidepressants, moved sequentially to give secondary and primary amino groups. On the other hand, tert- , narcoticbutyl groups analgesics, are usually local less anesthetics, prone to metabolic as well oxidative as other dealkylation drug classes. (Figure The 1). Intrin- order of prevalencesic secondary of the alky N-alkylamino groups in moieties–mostly alkylamino moieties methylamino–are is methyl also > ethylencountered > iso- in some propyl > tert-butyldrug > others. molecules. Methyl, Another ethyl, route and of isopropyl N-alkylamino groups moiety are usually metabolism found is in N drug-oxygenation, molecules as tertiarywhichN is, Nspecific-dimethylamino, to only tertiaryN ,NN,N-diethylamino,-dialkylamino moieties or N,N -diisopropylaminoeither open-chain aliphatic or moieties, respectively.heterocyclic In the [1]. metabolism of drug molecules containing N,N-dimethylamino, N,N-diethylamino andMechanistically,N,N-diisopropylamino CYP450-catalyzed moieties, N-dealkylation the alkyl groupsinvolves are as mostlya first step re- the hy- moved sequentiallydroxylation to give of secondary the carbon andatom primaryof the alkyl amino group groups. that is linked On the to the other nitrogen hand, atom (α- tert-butyl groupscarbon are usually atom). This less hydroxylated prone to metabolic metabolite oxidative is unstable. dealkylation It breaks spontaneously (Figure1). into two Intrinsic secondarymolecules:N-alkylamino the dealkylated moieties–mostly metabolite methylamino–are(e.g., an ), and also an aldehyde encountered (e.g., informalde- hyde after , acetaldehyde after deethylation, etc.) [1]. The reaction is shown some drug molecules. Another route of N-alkylamino moiety metabolism is N-oxygenation, for methyl and ethyl secondary in Figure 1, which can be aliphatic or heterocyclic which is specific to only tertiary N,N-dialkylamino moieties either open-chain aliphatic or (or aromatic). Similarly, tertiary amines are dealkylated in a similar way by consecutive heterocyclic [1]. hydroxylation of the alkyl groups at the carbon that is linked to the nitrogen atom [1].

N-dealkylation of a 2o methylamine o R NH2 1 Amine OH CYP 450 R NH CH3 R NH CH2 O 2o Methylamine HC Formaldehyde Intermediate H

N-dealkylation of a 2o ethylamine

o R NH2 1 Amine OH CYP 450 R NH CH2CH3 R NH CHCH3 O 2o Ethylamine Intermediate CH3 C Acetaldehyde H Figure 1. CYP 450 oxidativeFigure dealkylation1. CYP 450 oxidative of alkylamines. dealkylation of alkylamines.

Mechanistically,Depending CYP450-catalyzed on their class,N-dealkylation alkylamino moieties involves interact as with a first receptors step the or hy- via droxylation of thehydrogen carbon bonding, atom of ion-dipole, the alkyl ion-ion group and that van is der linked Waals to bindings the nitrogen as depicted atom in Figure 2 [2,3].

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(α-carbon atom). This hydroxylated metabolite is unstable. It breaks spontaneously into two molecules: the dealkylated metabolite (e.g., an amine), and an aldehyde (e.g., formalde- hyde after demethylation, acetaldehyde after deethylation, etc.) [1]. The reaction is shown for methyl and ethyl secondary amines in Figure1, which can be aliphatic or heterocyclic (or aromatic). Similarly, tertiary amines are dealkylated in a similar way by consecutive hydroxylation of the alkyl groups at the carbon that is linked to the nitrogen atom [1]. Depending on their class, alkylamino moieties interact with receptors or enzymes Molecules 2021, 26, x FOR PEER REVIEWvia bonding, ion-dipole, ion-ion and van der Waals bindings as depicted4 of 41 in

Figure2[2,3].

Drug Drug Drug N Drug H3C H CH3 N d- H C H - N 3 2 d + H C H N d 3 H3C H + + Hd Hd O - O O - O - C C d- O d O Ser Ser Asp Asp o o Protonated 3 amine Protonated 2 amine o ion-ion binding ion-ion binding Hydrogen-bond binding in 2 amines Binding of unionized and ionized amino groups in drug molecules to enzymes and receeptors Drug Enzyme or receptor N H3C CH3 van der Waal's binding ot the alkyl groups of H C CH N,N-dialkylamino moieties H3CCH3 3 3

Alanine/leucine FigureFigure 2.2. AlkylaminoAlkylamino moiety binding to receptors. receptors.

TheThe alkylamino-moieties-containingalkylamino-moieties-containing drugs drugs cited cited in in this this review review may may be be categorized categorized accordingaccording toto thethe receptorsreceptors upon which they act. act.

2.2. NeurotransmitterNeurotransmitter Reuptake Inhibitors TheThe drugsdrugs that contain contain alkylamino alkylamino moieties moieties in inthis this class class belong belong to four to four categories: categories: (i) (i)serotonin-norepinephrine serotonin-norepinephrine reup reuptaketake inhibitors (SNRI),(SNRI), (ii) (ii) selective selective norepinephrine norepinephrine reup- takereuptake inhibitors inhibitors (NRI), (NRI), (iii) selective (iii) selective serotonin serotonin reuptake reuptake inhibitors inhibitors (SRI), (SRI), and and (iv) (iv) serotonin- sero- norepinephrine-dopaminetonin-norepinephrine- reuptake reuptake inhibitors inhibitors (SNDRI). (SNDRI).

2.1.2.1. Serotonin-NorepinephrineSerotonin-Norepinephrine Reuptake Inhibitors (SNRI) (SNRI) ToTo thisthis subclasssubclass belongbelong the antidepressants imipramine imipramine and and amitriptyline, amitriptyline, whichwhich are are SNRISNRI withwith preference for SRI, are are respectively respectively metabolized metabolized by by NN-demethylation-demethylation toto desmipraminedesmipramine andand ,nortriptyline, (Figures 33 andand4 ,4, respectively). respectively). DesipramineDesipramine and nortriptylinenortriptyline havehave beenbeen developed developed into into drugs drugs of of their their own own rights; rights; they they have have preference preference for NRfor inhibitionNR inhibition over over SR inhibition.SR inhibition.

2.1.1.2.1.1. ImipramineImipramine and Amitriptyline BothBoth imipramineimipramine and and amitriptyline amitriptyline (Figures (Figures3 and3 and4, respectively)4, respectively) are are aliphatic aliphatic tertiary- ter- aminetiary-amine tricyclic tricyclic antidepressants. antidepressants. The The two two drugs drugs are are metabolized metabolized by byN N-demethylation-demethylation to equiactiveto equiactive secondary-amine secondary-amine metabolites, metabolites,desmipramine desmipramine and and nortriptyline, nortriptyline, respectively, respectively, asas shownshown in Figures 33 andand4 4[ [4–8].4–8]. The The latter latter two two drugs drugs are arefurther further metabolized metabolized by N by- Ndemethylation-demethylation to toinactive inactive primary primary amine amine metabolites metabolites [9]. Hydroxylation [9]. Hydroxylation is also is an also im- an importantportant metabolic metabolic pathway pathway of the of the four four drugs drugs (Figures (Figures 3 and3 and 4).4 ).

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HO 10 HO * OH 10 CYP2D6 * OHCH H 3 CYP2D6(6%) CH CH CH N ) CH2CH2CH2N CH CH CH NH 2 2 2 CH % 4 H 2 2 2 2 3 (6%)4 A 8 3 CH3 ( A CH3 CH CH CH N )P 2 CH2CH2CH2N N,N-didesmethyl-CH CH CH NH 2 2 2 %Y 4 Desmipramine 2 2 2 2 4C A P1 imipramine 10-HydroxyimipramineCH (8 3 Y A log P 3.90CH3 3 P C 2 pKa 10.02 N,N-didesmethyl- Y Desmipramine (Inactive) (Active) C P1 imipramine 10-Hydroxyimipramine 11 Y pKa 10.02 log P 3.90 9 C 1 (Inactive) (Active) 10 OH 8 11 2 FMO 9 1 CYP2D6 2 10 7 CH3 OHCH3 8 5 32 (10%) CH3 FMO 6 CYP2D6 2 CH2CH2CH2N CH2CH2CH2N O 7 CH3 CH3 CH2CH2CH2N 5 3 CH (10%) CH3 6 3 CH3 CH CH2CH2CH2N 2-HydroxyimpramineCH2CH2CH2N 3O CH2CH2CH2N CH Imipramine-N-oxide Imipramine 3 (active) CH3 CH3 2-Hydroxyimpramine (inactive) Dimethylamino- Imipramine-N-oxide pKa 9.2 log P 4.28 (active)UGT7B () propyl Imipramine Dimethylamino- (inactive) pKa 9.2 log P 4.28 2-HydroxydesipramineUGT7B (Imipraminoxide) propyl glucuronide (inactive) * Chiral carbon FMO: Flavin-containing monooxygenase 2-Hydroxydesipramine glucuronide (inactive) FigureFigure* Chiral 3. Metabolic carbon FMO: pathways pathways Flavin-containing of of imipramine. imipramine. monooxygenase Figure 3. Metabolic pathways of imipramine. HO 10 HO * 10 Nortriptyline * CH H 3 (Equiactive major CHCH CH N C 9 CHCH CH N Nortriptyline 2 2 CH YP 1 2 2 H metabolite) 3 2D CH3 6 P CH3 (Equiactive major CHCH CH N C Y 9 CHCH CH N pKa 10.47 2 2 YP C 1 2 2 metabolite) 10-Hydroxyamitriptyline 2D 2C CH3 6 10 11 P CH3 log P 4.43 9 1Y pKa 10.47 10-Hydroxyamitriptyline(active) C 8 10 11 2 log P 4.43 9 5 1 (active)11 4 10 MO 3 CH 9 1 F 87 2 3 6 5 11 CHCH2CH4 2N 8 10 2 O 3 CH 9 5 1 FM 7 3 4 6 CH3 3 CH AmitriptylineCHCH2CH2N CHCH CH NH 87 3 2 2 2 6 2 CHCH5 2CH4 2N O pKa 9.76 log P 4.81 CH3 3 CH Amitriptyline N,N-Didesmethyl-CHCH CH NH 7 CH3 2 2 2 6 CHCH CH N 3 pKa 9.76 log P 4.81HO amitriptyline Amitriptyline-N-oxide2 2 O 10 N,N-Didesmethyl- (Inactive) CH3 HO * amitriptyline Amitriptyline-N-oxide(Amitrptylinoxide) 10 CHCH(Inactive)2CH2N(CH3)2 (Amitrptylinoxide) 10-Hydroxynortriptyline * H * Chiral carbon (active) CHCH CH N DimethylaminopropylideneCHCH2CH2N(CH3)2 10-Hydroxynortriptyline 2 2 H * Chiral carbon CH3 Dimethylaminopropylidene (active) CHCH2CH2N CH Figure 4. Metabolic pathways of amitriptyline. 3 FigureFigure 4.4. Metabolic pathways pathways of of amitriptyline. amitriptyline. The four tricyclic drugs are SNRI with imipramine and amitriptyline beingTheThe more four active tricyclic as SRIs antidepressant antidepressant than NRIs and drugs drugs desmipramine are are SNRI SNRI with withand imipramine nortriptyline imipramine and being and amitriptyline amitriptyline more ac- beingtivebeing as more NRIs active activethan SRIs as as SRIs SRIs[10]. than Another than NRIs NRIs metabolicand and desmipramine desmipramine pathway andof imipramine nortriptyline and nortriptyline and being amitriptyline more being ac- more activeistive N -oxygenationas as NRIs NRIs than than resultingSRIs SRIs [10]. [10 inAnother]. the Another formation metabolic metabolic of imipramine-pathway pathway of imipramineN of-oxide imipramine and and amitriptyline- and amitriptyline amitriptylineN- isoxide,is NN-oxygenation-oxygenation respectively. resulting resulting The two in inN the-oxide the formation formation metabolites of of imipramine- imipramine-have been Ndeveloped-oxideN-oxide and as and amitriptyline- prodrugs amitriptyline- of im-N- N- oxide,ipramineoxide, respectively. and amitriptyline The The two two since N-oxideN -oxidethey metabolites (the metabolites N-oxide have metabolites) have been beendeveloped are developed bioreduced as prodrugs as in prodrugs vivo of im- to of imipraminetheipramine tertiary and amine and amitriptyline amitriptyline parent drugs, since since imipramine they they (the (theN -oxideandN -oxideamitriptyline metabolites) metabolites) [11]. are bioreduced are bioreduced in vivoin to vivo tothe the tertiaryReporting tertiary amine amine on parent comparison parent drugs, drugs, imipraminebetween imipramine imip andramine andamitriptyline amitriptyline and desmipramine, [11]. [11]. Rose and Westhead [12] found no difference between the two drugs in patients with primary de- ReportingReporting onon comparisoncomparison betweenbetween imipramineimipramine andand desmipramine, desmipramine, Rose Rose and and West- pression regarding antidepressive effect or . According to the authors [12], headWesthead [12] found [12] found no difference no difference between between the two the drugstwo drugs in patients in patients with with primary primary de- reactive and endogenous depression responded equally well to either drug. regardingpression regarding antidepressive antidepressive effect or effect onset or of onset action. of action. According According to the to authors the authors [12], reactive[12], The pKa and log p values of the imipramine and desmipramine are given in Figure andreactive endogenous and endogenous depression depression responded responded equally equally well to well either to either drug. drug. 3; the pKa and log p values of amitriptyline and nortriptyline are given in Figure 4. TheThe pKa and log p values of of the the imipramine imipramine and and desmipramine desmipramine are are given given in in Figure Figure 3;

the3; the pKa pKa and and log logp valuesp values of of amitriptyline amitriptylineand and nortriptylinenortriptyline are given in in Figure Figure 4.4.

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2.1.2.2.1.2. ClomipramineClomipramine ClomipramineClomipramine (Figure5 5),), aa 3-chloro3-chloro analoganalog ofof imipramine,imipramine, is a -derivativedibenzazepine-deriv- tricyclicative antidepressant (TCA). (TCA). It contains It contains a dimethylamino a dimethylamino propyl propyl moiety. moiety. Clomipramine Clomi- actspramine on both acts noradrenergic on both noradrenergic and serotonergic and sero transporters;tonergic transporters; however, however, with selectively with selec- for the serotonintively for transporterthe serotonin by transporter inhibiting by transporter inhibiting actiontransporter at presynaptic action at presynaptic neuronal sites neu- [13]. Inhibitionronal sites of [13]. the Inhibition serotonin of transmitter the serotonin by clomipramine transmitter by is clomipramine in contrast to is its in principal contrast activeto metabolite,its principalN active-desmethylclomipramine metabolite, N-desmethylclomipramine (Figure5), which principally(Figure 5), actswhich as principally antagonist of noradrenergicacts as antagonist transporter of noradrenergic receptor transporte [13,14]. Ther receptor effectiveness [13,14]. of The clomipramine, effectiveness compared of clom- to ipramine, compared to other TCAs, in the management of obsessive-compulsive disorder other TCAs, in the management of obsessive-compulsive disorder (OCD) may be related to (OCD) may be related to its relative specificity for serotonin reuptake system inhibition its relative specificity for serotonin reuptake system inhibition [14]. This observation may [14]. This observation may suggest that OCD might be caused, in part, by dysregulation suggest that OCD might be caused, in part, by dysregulation of the serotonergic system. of the serotonergic system. Further metabolic pathways of clomipramine include aromatic Further metabolic pathways of clomipramine include aromatic ring hydroxylation to active ring hydroxylation to active 8-hydroxyclomipramineand and N-oxygenation to clomipra- 8-hydroxyclomipramineand and N-oxygenation to clomipramine-N-oxide [15]. The pKa mine-N-oxide [15]. The pKa and log p values of clomipramine and N-desmethylclomipra- and log p values of clomipramine and N-desmethylclomipramine are given in Figure5. mine are given in Figure 5.

(Major ) N pKa 10.2 log P 4.5 Clomipramine CM) Cl 10 11 9 1 D6 P2 8 CY 9 2 C1 HO 5 P2 HN N Y 7 C 8 6 3 Cl 4 N pKa 9.2 log P 4.88 N-Desmethyl-CM Cl

Dimethylamino N HO propyl 8 HN N Cl N-Desmethyl-8-hydroxy-CM N (Active) Cl N Clomipramine-N-oxide 8-Hydroxy-CM (Inactive) N (Active) O The phenolic OH groups are further conjugated by glucuronic acid in phase II.

FigureFigure 5.5. MetabolicMetabolic pathways of of clomipramine. clomipramine.

2.1.3.2.1.3. VenlafaxineVenlafaxine VenlafaxineVenlafaxine (Figure 66)) is an antidepressant antidepressant drug drug that that acts acts as asboth both serotonin serotonin and and nore- nore- pinephrinepinephrine reuptakereuptake inhibitor. It It contains contains a adimethylaminomethyl dimethylaminomethyl moiety. moiety. The The metabolic metabolic pathwayspathways ofof venlafaxinevenlafaxine areare depicteddepicted in Figure 66[ [16–19].16–19]. While While OO-desmethylvenlafaxine-desmethylvenlafaxine is equiactiveis equiactive and and equipotent equipotent with with the the parent parent drug drug as as antidepressant antidepressant and and has has been been developed devel- intooped a druginto a ofdrug its ownof its right own underright under the name the name of , of desvenlafaxine,N-desmethylvenlafaxine N-desmethylven- islafaxine devoid is of devoid antidepressant of antidepressant activity activity [20,21]. [20,21]. The pKa The and pKa log andp logvalues p values of venlafaxine of venlafax- and desvenlafaxineine and desvenlafaxine are given are in given Figure in6 Figure. 6.

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H N CH3 H OH (Little activityN compared to venlafaxine)CH3 Dimethylaminomethyl OH (Little activity compared to venlafaxine) DimethylaminomethylH3CO C 4 Y CH3 A N-DesmethylvenlafaxineH3CO P P3 2 H N Y D C C 19CH A4 6 Y N 2C 3 pKa 9.783 log NP-Desmethylvenlafaxine 2.36 P H CH3 P YP 2 CH3 Y N r) C 9 DOH N C ino C1 pKa 9.78 log P 2.36 6 M CH3 P2 CH3 ( Y r) CH3 C ino OH HO M ( N 4 CH3 H3CO CY CH 3A HO PHO2 3 P N D6 OH CY 4 VenlafaxineH3CO CY CH 3A HO (56 P2 3 N,OP-Didesmethyl- %) D6 OH CY Venlafaxine ( venlafaxine N,O-Didesmethyl- pKa 8.91 56% HO ) log P 2.74 pKa 8.91 (Attenuated activity venlafaxine DesvenlafaxineHO log P 2.74 compared to desvenlafaxine)(Attenuated activity (Equiactive with venlafaxine)Desvenlafaxine compared to desvenlafaxine) (Equiactive with venlafaxine) Phenolic hydroxy groups (OH) are conjugated by glucuronic acid in phase II. Phenolic hydroxy groups (OH) are conjugated by glucuronic acid in phase II. Figure 6. Major metabolic pathways of venlafaxine. Figure 6. Major metabolic pathways of venlafaxine. Figure 6. Major metabolic pathways of venlafaxine. 2.1.4. Doxepin 2.1.4. Doxepin 2.1.4. Doxepin Doxepin (Figure 7) is a tricyclic antidepressant of the dibenzoxepine class. It contains a dimethylaminopropylidinoDoxepin (FigureDoxepin7) is a tricyclic (Figure moiety antidepressant 7) isand a tricyclic exists in ofantidepressant two the dibenzoxepine geometric of theforms: class.dibenzoxepine E Itand contains Z in class.the a It contains a dimethylaminopropylidino moiety and exists in two geometric forms: E and Z in the dimethylaminopropylidinoratio of 85:15, respectively moiety[22]. The and Z existsisomer in is two more geometric active forms:than theE andE isomerZ in the as ratioantide- of ratio of 85:15, respectively [22]. The Z isomer is more active than the E isomer as antide- 85:15,pressant respectively [23]. As far [22 ].as The theZ mechanismisomer is more of action active of than doxepin the E isomeris concerned, as antidepressant the E isomer [23 ].is pressant [23]. As far as the of doxepin is concerned, the E isomer is AsNRI far while as the the mechanism Z isomerof is actionSRI [24,25]. of doxepin However, is concerned, both isomers the E isomerare metabolized is NRI while by theN-de-Z NRI while the Z isomer is SRI [24,25]. However, both isomers are metabolized by N-de- isomermethylation is SRI [to24 give,25]. However,E- both and isomers Z-nordoxepin, are metabolized which by areN-demethylation active antidepressants to give to give E-nordoxepin and Z-nordoxepin, which are active antidepressants Eand-nordoxepin by N-oxidation and Z -nordoxepin,to give E-doxepin- whichN-oxide are active and antidepressants Z-doxepin-N-oxide, and bywhichN-oxidation are inactive to and by N-oxidation to give E-doxepin-N-oxide and Z-doxepin-N-oxide, which are inactive giveas antidepressantsE-doxepin-N-oxide [26]. andTheZ pKa-doxepin- and logN-oxide, p values which of E are-doxepin inactive and as antidepressantsE-N-nordoxepin [26 are]. as antidepressants [26]. The pKa and log p values of E-doxepin and E-N-nordoxepin are Thegiven pKa in andFigure log 7.p values of E-doxepin and E-N-nordoxepin are given in Figure7. given in Figure 7.

O O O O E-Doxepin E-Doxepin Z-Doxepin Z-Doxepin (85%) (85%) Dimethylamino (15%) (15%) pKa 8.96 Dimethylamino pKa 8.96 propylidino propylidino 6 log P 4.29 logD P 4.29 6 C 2 N D N N Y N C P 9 2 9 P Y Y 1 P 1 2 P C Y C C 2 C 2 C 2 1 C O P P 9 O19 O Y O Y C C O O O O

N N N N H H H Z-DesmethyldoxepinH Z-Desmethyldoxepin N N N N E-DesmethyldoxepinE-Desmethyldoxepin O O O O (Z-Nordoxepin)(Z-Nordoxepin) (E-Nordoxepin) (E-Nordoxepin) (Active) (Active) E-Doxepin-N-oxideE-Doxepin-Z-Doxepin-N-oxideN-oxideZ-Doxepin-N-oxide pKa 9.75 log P 3.75pKa 9.75 log P 3.75 (Active) (Active) (Inactive) (Inactive) Figure 7. Metabolic pathways of doxepin. FigureFigure 7.7.Metabolic Metabolic pathwayspathways ofof doxepin.doxepin.

2.2.2.2. SelectiveSelective NorepinephrineNorepinephrine2.2. Selective Norepinephrine ReuptakeReuptake InhibitorsInhibitors Reuptake (NRIs)(NRIs) Inhibitors (NRIs) 2.2.1.2.2.1. MaprotilineMaprotiline2.2.1. Maprotiline MaprotilineMaprotiline (Figure(FigureMaprotiline8 8)) is is a a tetracyclic(Figure 8) antidepressant.is antidepressant. a tetracyclic antidepressant. ItIt containscontains aa secondary secondaryIt contains methy-amethyl- secondary methyl- laminopropylaminopropyl moiety.aminopropyl The The mechanism mechanismmoiety. The of ofmechanism action action of of maprotiline maprotilineof action of involvesmaprotiline involves selective selective involves norepi- nore- selective norepi- pinephrine neuronal reuptake inhibition. The metabolic pathways of maprotiline are de- picted in Figure8 with N-desmethylmaprotiline forming the major active metabolite [27–31].

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nephrine neuronal reuptake inhibition. The metabolic pathways of maprotiline are de- Molecules 2021, 26, 1917 nephrine neuronal reuptake inhibition. The metabolic pathways of maprotiline8 of 40 are de- picted in Figure 8 with N-desmethylmaprotiline forming the major active metabolite [27– picted in Figure 8 with N-desmethylmaprotiline forming the major active metabolite [27– 31]. TheThe log log p pvalues values of ofmaprotiline maprotiline and and N-desmethylmaprotiline N-desmethylmaprotiline in addition in addition to the pKato the pKa Thevalue log ofpofvalues maprotiline maprotiline of maprotiline are are given given and inN -desmethylmaprotilineFigurein Figure 8. No 8. valueNo value has in been additionhas beenfound to thefound for pKa the valuefor pKa the value pKa of value of ofN-desmethylmaprotiline; maprotiline are given in Figure however, however,8. No it value can it canbe has es be beentimated es foundtimated to forbe thetohigher be pKa higher than value that ofthanN of- thatmapro- of mapro- desmethylmaprotiline;tiline. however, it can be estimated to be higher than that of maprotiline.

NH2 NH2

Methylaminopropyl log P 3.24 9 log P 3.24 C1 9 P2 C1 H CY P2 H CY N-Desmethylmaprotiline N N-Desmethylmaprotiline NCH3 CH (Active) 3 (Active) 2 1 H 1 2 CY H 3 P N N H C2D H CH YP6 CHN3 3 N 4 3 2D 6 OH CH3 CH3 Maprotiline4 2 OH+ Maprotiline pKa 10.54 log P 4.37 2 + 3 OH pKa 10.54 log P 4.37 OH 2-Hydroxymaprotiline 3-Hydroxymaprotiline 3 2-Hydroxymaprotiline Figure 8. Major metabolic pathways of maprotiline. 3-Hydroxymaprotiline

FigureFigure 8. 8.Major Major metabolic metabolic pathways pathways of maprotiline. of maprotiline. 2.2.2. Atomoxetine 2.2.2.2.2.2. AtomoxetineAtomoxetine Atomoxetine (Figure 9) is a selective NRI used to treat attention deficit hyperactivity disorderAtomoxetine (ADHD). (Figure It contains9) is a selective a secondary NRI used ethylmethylamino to treat attention deficit moiety hyperactivity and is metabolized Atomoxetine (Figure 9) is a selective NRI used to treat attention deficit hyperactivity disorderas per the (ADHD). pathways It contains shown a secondaryin Figure 9 ethylmethylamino [32–38]. While aromatic-ring moiety and is metabolizedhydroxylation does asdisorder per the pathways (ADHD). shown It contains in Figure a9 [secondary32–38]. While ethylmethylamino aromatic-ring hydroxylation moiety doesand is metabolized not affect the blockade of the NET and produces an equipotent metabolite to the parent not affect the blockade of the NET and produces an equipotent metabolite to the parent drugas per [35], the N pathways-demethylation shown causes in Figure nearly 9 20-fold [32–38]. loss While of pharmacologic aromatic-ring activity hydroxylation with re- does drugnot affect [35], N -demethylationthe blockade of causes the nearlyNET and 20-fold produces loss of pharmacologic an equipotent activity metabolite with to the parent respectspect to to atomoxetine [ 37[37].]. The The pKa pKa and and log plogvalues p values of atomoxetine of atomoxetine and 4-hyroxy- and 4-hyroxy-N- N- desmethylatomoxetinedesmethylatomoxetinedrug [35], N-demethylation and and the pKathe causes valuepKa value of nearlyN-desmethylatomoxetine of N -desmethylatomoxetine20-fold loss of arepharmacologic given are in Figure given9 . activityin Figure with re- No9.spect No log plogtovalue atomoxetinep value has been has found been [37]. forfound TheN-desmethylatomoxetine; forpKa N -desmethylatomoxetine;and log p values however, of itatomoxetine canhowever, be estimated it can and be 4-hyroxy- esti- N- tomateddesmethylatomoxetine be lower to be than lower that ofthan atomoxetine. that and of theatomoxetine. pKa value of N-desmethylatomoxetine are given in Figure 9. No log p value has been found for N-desmethylatomoxetine; however, it can be esti- Primary mated to be lower than that of atomoxetine.(20-fold less active than amine H2NO Secondary atomoxetine as NET blocker) methylamino Primary pKa 10.13 9 C C1 H NOY (20-fold less active than Secondary amine P2 2 P2 H CY r) D6 atomoxetine as NET blocker) 1 ino H NO NOmethylamino (M N-Desmethyl- 2 6 2 pKa 10.13 19 atomoxetine C 5 3 2C Y (M P P2 9 4 a Y H ) C1D H joCr or 2 6 NO1 ) iNOn YP H2NO CY (M N-Desmethyl-C 6 2P2 4 Atomoxetine D6 atomoxetine OH 5 3 (M 4 N-Desmethyl-19 pKa 9.8 4 ajo H OH 2C r) NO YP 4-hydroxyatomoxetine log P 3.81 CY C P2 4 Atomoxetine D6 4-Hydroxyatomoxetine pKa 9.59 logOH P 2.32 (Equipotent to atomoxetine 4 N-Desmethyl- pKa 9.8 as NET blocker) OH 4-hydroxyatomoxetine log P 3.81 (The phenolic4-Hydroxyatomoxetine OH groups are glucuronide conjugatedpKa 9.59 in phaselog II. P) 2.32 (Equipotent to atomoxetine FigureFigure 9. 9. Metabolic pathways of atomoxetine. Metabolic pathways of atomoxetine.as NET blocker)

(The phenolic OH groups are glucuronide conjugated in phase II.) Figure 9. Metabolic pathways of atomoxetine.

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2.3.2.3. Selective Selective Serotonin serotonin Reuptakereuptake Inhibitorsinhibitors (SSRI) 2.3.1.2.3.1. Fluoxetine Fluoxetine InIn contrast contrast to to TCAs, TCAs, fluoxetine fluoxetine (Figure (Figure 10 10)) is is a a selective selective serotonin serotonin reuptake inhibitor (SSRI).(SSRI). It It is is used used for for the the treatment treatment of depression,of depression, bulimia bulimia nervosa nervosa and and obsessive-compulsive obsessive-compul- disordersive disorder (OCD) (OCD) [39]. [39]. Structurally,Structurally, fluoxetine fluoxetine is characterizedis characterized by the by presence the presence of a methylaminopropyl of a methylaminopropyl group, asgroup, depicted as depicted in Figure in8. Figure Fluoxetine 8. Fluoxetine is extensively is extensively metabolized metabolized in the . in the The liver. only The identi- only fiedidentified active metabolite,active metabolite, norfluoxetine, norfluoxetine, is formed is byformedN-demethylation by N-demethylation of fluoxetine of fluoxetine [39–43]. Fluoxetine[39–43]. Fluoxetine is a racemic is a mixtureracemic ofmixture two enantiomers: of two enantiomers:R and S -fluoxetine.R and S-fluoxetine.S-fluoxetine S-fluox- is slightlyetine is moreslightly potent more in potent the inhibition in the inhibition of serotonin of serotonin reuptake reuptake than R than-fluoxetine. R-fluoxetine. The dif- The ferencedifference is, however,is, however, much much more more pronounced pronounced for for the the active active metabolite metaboliteS -norfluoxetine,S-norfluoxetine, whichwhich has has about about twenty-fold twenty-fold higherhigher serotonin-reuptakeserotonin-reuptake blockingblocking potencypotency thanthan thetheR R-- norfluoxetinenorfluoxetine [[43].43]. The four four compounds compounds (R (R- -and and S-fluoxetineS-fluoxetine and and their their corresponding corresponding me- metabolites)tabolites) differ differ also also in their in their kinetics. kinetics. After After several several weeks weeks of treatment, of treatment, the plasma the plasma concen- concentrationtration of both of S both-enantiomersS-enantiomers is about is abouttwo times two timeshigher higher than the than concentration the concentration of the of R- theenantiomersR-enantiomers [43]. [43]. FluoxetineFluoxetine has has now now largely largely replaced replaced older older and an lessd less safe safe drugs drugs such such as tricyclicas tricyclic antide- anti- pressants.. Different Different cytochrome cytochro P450me P450 isoforms isoforms are involved are involved in the in metabolism the metabolism of fluoxetine, of fluox- however,etine, however, the main the active main active metabolite, metabolite, norfluoxetine, norfluoxetine, is produced is produced by the by CYP2D6 the CYP2D6 action ac- intion the in human the human liver liver [39– 43[39–43].]. The The pKa pKa and and log logp values p values of of fluoxetine, fluoxetine, norfluoxetine norfluoxetine and and norfluoxetinenorfluoxetine glucuronide glucuronide are are given given in in Figure Figure 10 10..

F3C Methylaminopropyl F3C Norfluoxetine CYP2D6 O CYP2C9 O (Sole phase I metabolite; active) CYP3A4 * N * NH2 H C Y P 2 pKa 9.77 D R/S-Fluoxetine 6 pKa 9.8 log P 4.17 log P 3.74 F3C pKa 4.68 OH HO OH Both R- and S-fluoxetine are metabolized by O H N-demethylation to give active N-desmethyl N OH metabolites. * O O O

Norfluoxetine glucuronide pKa 3.03 log P 0.45 FigureFigure 10. 10.Metabolic Metabolic pathway pathway of of fluoxetine. fluoxetine.

2.3.2.2.3.2. Citalopram/Escitalopram Citalopram/Escitalopram CitalopramCitalopram (Figure (Figure 11 11)) is is a a SSRI. SSRI. It It is is used used to to treat treat depression depression for for panic panic attacks. attacks. Citalo- Cital- pramopram is ais chiral a chiral drug drug [44 ].[44]. The The substantially substantially more more active activeS-enantiomer S-enantiomer has been has developedbeen devel- intooped a druginto a of drug its own of its right own under right theunder name the of na escitalopram.me of escitalopram. As shown As inshown Figure in 11Figure, citalo- 11, pramcitalopram contains contains a dimethylaminopropyl a dimethylaminopropyl moiety moiety and is primarilyand is primarily sequentially sequentially metabolized metab- byolized oxidative by oxidativeN-demethylation N-demethylation to N-demethylcitalopram to N-demethylcitalopram (DCT) (DCT) by CYP3A4 by CYP3A4 and to andN,N to- didemethylcitalopramN,N-didemethylcitalopram (DDCT) (DDCT) by CYP2D6 by CYP2D6 [45–47 [45–47].]. Other Other metabolites metabolites include include inactive inac- citalopram-tive citalopram-N-oxideN-oxide and a and deaminated a deaminated propionic propionic acid derivative acid derivative (Figure (Figure 11). In 11). humans, In hu- unchangedmans, unchanged citalopram citalopram is the predominant is the predominant compound compound in plasma in [47 plasma]. At steady [47]. state,At steady the concentrations of citalopram’s metabolites, DCT and DDCT, in plasma are approximately state, the concentrations of citalopram’s metabolites, DCT and DDCT, in plasma are ap- one-half and one-tenth, respectively, that of the parent drug [47]. proximately one-half and one-tenth, respectively, that of the parent drug [47]. studies show that citalopram is at least 8 times more potent than its metabolites In vitro studies show that citalopram is at least 8 times more potent than its metabo- in inhibiting serotonin reuptake [47], suggesting that the metabolites evaluated do not lites in inhibiting serotonin reuptake [47], suggesting that the metabolites evaluated do likely contribute significantly to the antidepressant actions of citalopram. not likely contribute significantly to the antidepressant actions of citalopram.

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The pKa and log p values of citalopram and norcitalopram are given in Figure 11. TheThe pKapKa andand loglog pp valuesvalues ofof citalopramcitalopram andand norcitalopramnorcitalopram areare givengiven inin FigureFigure 11.11.

NCNC DimethylaminopropylDimethylaminopropyl NCNC OO OO ** NN ** OO CYP2C19CYP2C19 OHOH CitalopramCitalopram (CT)(CT)

F F RR CYP3A4 FF AA CYP3A4 OO M pKapKa 9.859.85 CitalopramCitalopram propionicpropionic acidacid M H loglog PP 3.763.76 H CYP2D6 NH (Inactive) NN CYP2D6 NH22 (Inactive) RCHRCH2 RCHRCH22 2 NC NC NN-Desmethyl--Desmethyl- N,NN,N-didesmethyl--didesmethyl- OO OO citalopramcitalopram (DCT)(DCT) citalopramcitalopram (DDCT)(DDCT) ** NN (Active)(Active) (Active)(Active) Citalopram-Citalopram-NN-oxide-oxide pKapKa 10.5410.54 log log PP 3.383.38 (Inactive)(Inactive) FF MAO: Monoamino oxidase MAO: Monoamino oxidase ** ChiralChiral centercenter FigureFigureFigure 11. 11.11.Metabolic MetabolicMetabolic pathways pathwayspathways of ofof citalopram. citalopram.citalopram.

2.3.3.2.3.3.2.3.3. Sertraline SertralineSertraline SertralineSertralineSertraline (Figure (Figure(Figure 12 12)12)) is isis an anan antidepressant antidepressantantidepressant of ofof the thethe selective selectiveselective serotonin serotoninserotonin reuptake reuptakereuptake inhibitor inhibi-inhibi- (SSRI)tortor (SSRI)(SSRI) class. class.class. It is primarily ItIt isis primarilyprimarily prescribed prescribedprescribed for major forfor major depressivemajor depressivedepressive disorder disorderdisorder (MDD) (MDD)(MDD) in adult inin outpa- adultadult tientsoutpatientsoutpatients as well as as wellwell obsessive-compulsive asas obsessiobsessive-compulsiveve-compulsive disorder disorderdisorder (OCD), panic(OCD),(OCD), disorder, panicpanic disorder,disorder, and social andand anxiety socialsocial disorder,anxietyanxiety disorder,disorder, in both adults inin bothboth and adultsadults children. andand children.children. In 2013, it InIn was 2013,2013, the itit most waswas the prescribedthe mostmost prescribedprescribed antidepressant antide-antide- andpressantpressant second andand most secondsecond prescribed mostmost prescribedprescribed psychiatric psychiatripsychiatri medicationcc medicationmedication (after ) (after(after alprazolam)alprazolam) on the U.S. onon thethe retail U.S.U.S. market,retailretail market,market, with over withwith 41 overover million 4141 millionmillion prescriptions prescriptionsprescriptions annual inannualannual 2013 [inin48 2013].2013 Sertraline [48].[48]. SertralineSertraline contains containscontains a methy- aa laminomethylaminomethylamino moiety moiety andmoiety is metabolized andand isis metabolizedmetabolized by N-demethylation byby NN-demethylation-demethylation to N- toto NN-desmethylsertraline-desmethylsertraline [48–50]. The[48–50].[48–50]. metabolite TheThe metabolitemetabolite is 5 to 10 is timesis 55 toto less 1010 timestimes potent lessless as potent SSRIpotent than asas SSRISSRI the parent thanthan thethe drug parentparent and drug accordinglydrug andand ac-ac- itscordinglycordingly clinical its contributionits clinicalclinical contributioncontribution is negligible isis negligiblenegligible [48]. The [48].[48]. pKa TheThe and pKapKa log andandp values loglog pp valuesvalues of sertraline ofof sertralinesertraline and norsertralineandand norsertralinenorsertraline are given areare givengiven in Figure inin FigureFigure 12. 12.12.

SecondarySecondary H methylaminomethylamino H H N NN H22N 5-10-fold5-10-fold lessless potentpotent * ** * ** thanthan sertralinesertraline asas SSRISSRI ** CYP3A4CYP3A4 Cl ClCl CYP2B6CYP2B6 Cl Cl ClCl Cl ** ChiralChiral centercenter 11SS,4,4SS-Sertraline-Sertraline 11SS,4,4SS-Norsertraline-Norsertraline pKapKa 9.859.85 loglog PP 5.155.15 ((NN-desmethylsertraline)-desmethylsertraline) pKapKa 9.739.73 loglog PP 4.724.72 FigureFigureFigure 12. 12.12.Metabolism MetabolismMetabolism of ofof sertraline. sertraline.sertraline.

2.3.4.2.3.4.2.3.4. Fenfluramine FenfluramineFenfluramine FenfluramineFenfluramineFenfluramine (Figure (Figure(Figure 13 13)13)) is isis a aa serotonin serotoninserotonin reuptake reupreuptaketake inhibitor inhibitorinhibitor that thatthat also alsoalso acts actsacts by byby causing causingcausing releasereleaserelease of ofof 5-HT 5-HT5-HT from fromfrom stores storesstores [[51,[51,51,5252].52].]. ItIt was was as as appetite appetite inhibiinhibi inhibitortortor beforebefore before beingbeing being withdrawn;withdrawn; withdrawn; itit ithas,has, has, however,however, however, beenbeen been reinstatedreinstated in in the the treatmenttreatmentreatmentt ofofof DravetDravetDravet syndromesyndromesyndrome (a (a(a type typetype of ofof epileptic epilepticepileptic disease)disease)disease) [ 52 [52].[52].]. Fenfluramine FenfluraFenfluraminemine contains containscontains an anan aliphatic aliphaticaliphatic secondary secondarysecondary ethylaminopropyl ethylaminopropylethylaminopropyl moiety moietymoiety and andand isisis metabolized metabolizedmetabolized to toto the thethe main mainmain active activeactive product, product,product,N NN-desmethylfenfluramine-desmethylfenfluramine-desmethylfenfluramine (norfenfluramine) ()(norfenfluramine) (Figure(Figure.(Figure. 13 13)13))[53 [53,54].[53,54].,54]. The TheThe pKa pKapKa and andand log loglogp ppvalues valuesvalues of ofof fenfluramine fenfluraminefenfluramine and andand norfenfluramine norfenfluraminenorfenfluramine are areare givengivengiven in inin Figure FigureFigure 13 13.13..

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EthylaminopropylEthylaminopropyl

F F FF F HH F N CYP1A2CYP1A2 F N F NHNH2 F CYP2B6CYP2B6 2 F FF CYP2D6CYP2D6 Fenfluramine NN-Desethylfenfluramine-Desethylfenfluramine pKa 9.92 log P 3.47 pKa 9.92 log P 3.47 (Norfenfluramine)(Norfenfluramine) (Active)(Active) pKa 9.99 log P 2.68 pKa 9.99 log P 2.68 Figure 13. Metabolism of fenfluramine. FigureFigure 13. 13.Metabolism Metabolism of of fenfluramine. fenfluramine.

3.3.3. Dopaminergic,Dopaminergic, Dopaminergic, Serotonergic,Serotonergic, Serotonergic, AdrenergicAdrenergic Adrenergic and and andN N N-methyl--methyl--methyl-DDD-aspartate-aspartate-aspartate (NMDA)(NMDA) (NMDA) Recep- Recep- Receptortortor Blockers Blockers Blockers 3.1. Loxapine/Amoxapine 3.1.3.1. Loxapine/Amoxapine Loxapine/Amoxapine Loxapine (Figure 14) is a neuroleptic of the dibenzoxazepine class. It is mainly a LoxapineLoxapine (Figure (Figure 14) 14) is is a a neuroleptic neuroleptic of of the the dibenzoxazepine dibenzoxazepine class. class. It It is is mainly mainly a a do- do- , but also a serotonin 5-HT2 blocker, used in the management of paminepamine antagonist, antagonist, but but also also a a serotonin serotonin 5-HT2 5-HT2 blocker, blocker, used used in in the the management management of of schiz- schiz- schizophreniaophrenia [55]. [ 55It contains]. It contains a tertiary a tertiary heterocyclic heterocyclic methylamino methylamino group group and is andmetabolized is metab- in olizedophreniain vivo [55].to It Ncontains-desmethylloxapine a tertiary heterocyclic and 8-hydroxyloxapine methylamino group [56– 58and], twois metabolized compounds in vivovivo to to N N-desmethylloxapine-desmethylloxapine and and 8-hydroxyloxapin 8-hydroxyloxapinee [56–58], [56–58], two two compounds compounds with with anti- anti- withdepressant antidepressant activity; activity; however, however, only desmet only desmethylloxapinehylloxapine has shown has shownfavorable favorable pharmacody- phar- macodynamic, activity; pharmacokinetic however, only and desmet toxicologicalhylloxapine properties has shown to be favorable developed pharmacody- into a fully- namic, pharmacokinetic and toxicological properties to be developed into a fully-fledged fledgednamic, pharmacokinetic drug under the name and toxi of amoxapine.cological properties The pKa to and be developed log p values into of a loxapine fully-fledged and drug under the name of amoxapine. The pKa and log p values of loxapine and N- Ndrug-desmethylloxapine under the name (amoxapine) of amoxapine. are given The inpKa Figure and 14log. p values of loxapine and N- desmethylloxapinedesmethylloxapine (amoxapine (amoxapine)) are are given given in in Figure Figure 14. 14.

Loxapine N Tertiary heterocyclic Loxapine N Tertiary heterocyclic pKapKa 7.18 7.18 methylaminomethylamino log P 3.6 N log P 3.6 N 9 N 1 9 N 1 Cl N N Cl C N N 2 CYYP 1A2 8 5 2 P 2D YP1A 8 5 2 2D 6 CYP 7 O 3 6 N N C 7 O 4 3 N N 6 4 N N 6 N N Cl CYP3A4 Cl HO Cl CYP3A4 H Cl HO HN N 8 O 8 O O O HO 7 N HO 7 N 8-Hydroxyloxapine N 7-Hydroxyloxapine 8-Hydroxyloxapine N Cl 7-Hydroxyloxapine (active) Cl (active) (active)(active) O O NN-Desmethylloxapine-Desmethylloxapine (Amoxapine) (Amoxapine) (active) pKa 8.63 log P 3.4 (active) pKa 8.63 log P 3.4 FigureFigureFigure 14. 14. 14.Metabolic Metabolic Metabolic pathwayspathways pathways of of of loxapine. loxapine. loxapine. 3.2. Clozapine 3.2.3.2. Clozapine Clozapine Clozapine (Figure 15) is a dibezodiazepine atypical neuroleptic agent ClozapineClozapine (Figure (Figure 15) 15) is is a a dibezodiazepine dibezodiazepine atypical atypical neuroleptic neuroleptic antipsychotic antipsychotic agent agent used in the treatment of . It acts as an antagonist of dopamine and serotonin usedused in in the the treatment treatment of of schizophrenia. schizophrenia. It It acts acts as as an an antagonist antagonist of of dopamine dopamine and and serotonin serotonin receptors [59]. It contains a heterocyclic tertiary methylamino moiety and is metabolized in receptorsreceptors [59].It [59].It contains contains a a heterocyclic heterocyclic tertiary tertiary methylamino methylamino moiety moiety and and is is metabolized metabolized humans to N-, which has limited antipsychotic activity and clozapine- inin humans humans to to N N-desmethylclozapine,-desmethylclozapine, which which has has limite limitedd antipsychotic antipsychotic activity activity and and clozap- clozap- N-oxide, which is inactive (Figure 15)[60–63]. The pKa and log p values of clozapine and ine-ine-NN-oxide,-oxide, which which is is inactive inactive (Figure (Figure 15) 15) [60–63]. [60–63]. The The pKa pKa and and log log p p values values of of clozapine clozapine N-desmethylclozapine are given in Figure 15. andand N N-desmethylclozapine-desmethylclozapine are are given given in in Figure Figure 15. 15.

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HeterocyclicHeterocyclic tertiary tertiary methylaminomethylamino OO HH NN NN NN

NN NN NN NN NN NN ClCl ClCl ClCl CYP1A2CYP1A2 CYP3A4CYP3A4 NN NN NN HH HH HH Clozapine-Clozapine-NN-oxide-oxide ClozapineClozapine NN-Desmethylclozapine-Desmethylclozapine (Inactive)(Inactive)pKapKa 7.35 7.35loglog P P 3.4 3.4 (Limited (Limited activity) activity) pKapKa 8.83 8.83loglog P P 3.02 3.02 FigureFigureFigure 15.15. 15. MetabolicMetabolic Metabolic pathwayspathways pathways ofof of clozapine.clozapine. clozapine.

3.3.3.3.3.3. Mianserin Mianserin MianserinMianserinMianserin (Figure(Figure (Figure 1616) 16)) isis is tetracyclictetracyclic tetracyclic second-generationsecond-generation second-generation typicaltypical typical antidepressantantidepressant antidepressant usedused used inin in thethethe treatmenttreatment treatment of of of depression. depression. depression. It mainlyIt It mainly mainly acts acts acts as aas serotonin-receptoras a a serotonin-receptor serotonin- antagonist antagonist and to and aand lesser to to a a extentlesserlesser extent as extent norepinephrine as as norepinephrine norepinephrine antagonist antagonist antagonist [64]. Mianserin [6 [64].4]. Mianserin Mianserin contains contains contains a heterocyclic a a heterocyclic heterocyclic tertiary tertiary methy- tertiary laminomethylaminomethylamino moiety moiety andmoiety is metabolizedan andd is is metabolized metabolized by N-demethylation, by by N N-demethylation,-demethylation, aromatic-ring aromatic-ring aromatic-ring hydroxylation hydroxyla- hydroxyla- and Ntiontion-oxygenation and and N N-oxygenation-oxygenation as depicted as as indepicted depicted Figure 16in in [Figure 65Figure–68 ].16 16 The [65–68]. [65–68]. blocking The The ofblocking blocking the two of receptorsof the the two two receptors is receptors shared toisis shared a shared lesser to extentto a a lesser lesser by extentN extent-desmethylmianserin by by N N-desmethylmianserin-desmethylmianserin and 8-hyroxymianserin. and and 8-hyroxymianserin. 8-hyroxymianserin. The N-oxide The The metabo-N N-oxide-oxide litemetabolitemetabolite is inactive is is inactive [66inactive]. The [66]. pKa[66]. The andThe pKa logpKap and valuesand log log ofp p mianserinvalues values of of mianserin andmianserinN-desmethylmianserin and and N N-desmethylmi--desmethylmi- are givenanserinanserin in are Figureare given given 16 .in in Figure Figure 16. 16.

HH NN-Desmethylmianserin-Desmethylmianserin HeterocyclicHeterocyclic tertiary tertiary NN (Active)(Active) methylaminomethylamino NN pKapKa 8.84 8.84 log log P P 3.54 3.54 ** MianserinMianserin HH NN NN 6 6 pKapKa 6.92 6.92 2D2D YYPP loglog P P 3.83 3.83 NN CC CCYYP2PD2D11 NN ** NN ** CCYYPP2D2D44 CC YYP2P2 NN HOHO DD33 ** 8 8 CCYYP2PD2D11 CCYY P2PD2D44 8-Hydroxy-8-Hydroxy-NN- - OO HOHO 8 8 desmethylmianserindesmethylmianserin NN (Active)(Active) 8-Hydroxymianserin8-Hydroxymianserin NN (Active)(Active) ** Mianserin-Mianserin-NN-Oxide-Oxide * *Chiral Chiral center center (Inactive)(Inactive)

TheThe meabolizing meabolizing isozymes isozymes are are selective selective for for the the R R enantiomer enantiomer of of mianserin. mianserin. FigureFigureFigure 16.16. 16. MetabolicMetabolic Metabolic pathwayspathways pathways ofof of mianserin.mianserin. mianserin.

3.4.3.4.3.4. Mirtazapine Mirtazapine MirtazapineMirtazapineMirtazapine (Figure (Figure 1717) 17)) isis is aa a pyrazinopyridobenazepinepyrazinopyridobenazepine pyrazinopyridobenazepine that that acts acts as as atypicalatypical atypical antide-antide- antide- pressantpressantpressant throughthrough through twotwo two mechanisms:mechanisms: mechanisms: itit it antagonizingantagonizing antagonizing 5-HT25-HT2 5-HT2 andand and 5-HT35-HT3 5-HT3 receptorsreceptors receptors asas as wellwell well asas as ititit increasesincreases increases noradrenalinenoradrenaline noradrenaline releaserelease release intointo into thethe the synapsesynapse synapse [[69].69 [69].]. MirtazapineMirtazapine Mirtazapine containscontains contains aa a tertiarytertiary tertiary heterocyclicheterocyclicheterocyclic methylaminomethylamino methylamino moiety.moiety. moiety. AsAs As shownshown shown inin in FigureFigure Figure 1717, 17,, mirtazapinemirtazapine mirtazapine isis is metabolizedmetabolized metabolized byby by NNN-demethylation-demethylation-demethylation toto to NN N-desmethylmirtazapine,-desmethylmirtazapine,-desmethylmirtazapine, aromatic-ringaromatic-ring aromatic-ring hydroxylationhydroxylation hydroxylation atat at positionposition position 88 8 tototo 8-hydrpxymirtazapine8-hydrpxymirtazapine 8-hydrpxymirtazapine andand and NN N-oxidation-oxidation-oxidation toto to mirtazapine-mirtazapine- mirtazapine-NNN-oxide-oxide-oxide [[70,71]. 70[70,71].,71]. TheThe The firstfirst first twotwo two metabolitesmetabolitesmetabolites havehave have muchmuch much lowerlower lower antidepressantantidepressa antidepressantnt activityactivity activity thanthan than mirtazapinemirtazapine mirtazapine whilewhile while thethe the NN N-oxide-oxide-oxide metabolitemetabolitemetabolite isis is inactiveinactive inactive [[70]. 70[70].]. Further, Further, mirtazapinemirtazapine mirtazapine is is a a chiral chiral drug drug as as indicated indicated in in Figure Figure 1818. 18.. TheTheThe levolevo levo enantiomerenantiomer enantiomer ofof of mirtazapinemirtazapine mirtazapine hashas has aa a two-foldtwo two-fold-fold eliminationelimination elimination half-lifehalf-life half-life longerlonger longer thanthan than thethe the dextrodextrodextro enantiomerenantiomer enantiomer [[70]. 70[70].]. The The levole levovo enantiomer,enantiomer, enantiomer, therefore,therefore, therefore, achievesachi achieveseves plasmaplasma plasma levelslevels levels thatthat that areare are

MoleculesMolecules 20212021, 26, 26, ,x 1917 FOR PEER REVIEW 13 of 40 13 of 41

Molecules 2021, 26, x FOR PEER REVIEWabout 3 times as high as that of the dextro enantiomer [70]. The pKa and log p 13values of 41 of about 3 times as high as that of the dextro enantiomer [70]. The pKa and log p values of mirtazapinemirtazapine and andN -desmethylmirtazapineN-desmethylmirtazapine are given are given in Figure in Figure 17. 17.

about 3 times as high as that of the dextro enantiomer [70]. The pKaH and log p values of pKa 8.75 mirtazapine andHeterocyclic N-desmethylmirtazapine tertiary are given in Figure 17. N methylamino log P 2.82 N H N Heterocyclic tertiary pKa 8.75 N * O methylaminopKa 7.7 N 1 log P 2.82 N N A4 N 3 P3 * O 4 N CY N pKa 7.7 14N 1 N N-Desmethylmirtazapine N N * 4 * 133 3A7 (Active) YP 14 4 N C CN-Desmethylmirtazapine N * N 8 Y N * N FMO 10 P2 13 11 7 9 C D6 (Active) C Y 8 Y P1 N Mirtazapine-N-oxideFMO 10 P2 A2 N 11 Mirtazapine9 C D6 * N YP Mirtazapine-(Inactive)N-oxide 1A N Mirtazapinelog P 3.21 2 * N (Inactive) log P 3.21 8 OH 8-Hydroxxymirtazapine8 OH 8-Hydroxxymirtazapine (Active) (Active) Figure 17. Metabolic pathways of mirtazapine. FigureFigure 17.17. Metabolic pathways pathways of of mirtazapine. mirtazapine.

CH3 CH3 2' N2' N Olanzapine-Olanzapine-N-oxideN-oxide 4' 4' N 6' 5'N O6' O pKa 8.83 (Inactive) 5 5 5' pKa 8.83 (Inactive) N 1' 1' 6 6 N 3 3 3' 3' 2 NH N CH3 10 CH 2 2' 4' N CH N S10 3 2' NH 3 1 CH3 log P 3.01 N 4' N H N S 5' 5 9 1 log P1' 3.01 N N N H N 6' 5' 6 5 3 9 1' N N 6' 6 2 3 10 CH OH CH3 2 pKa 7.4 2 N S N S 1 2 1A H10 CH OH P H CH3 9 N S 2 pKa 7.4 CY 2 N S 1 3' 4'-N-Desmethylolanzapine1A H 2' P H 2-Hydroxymethylolanzapine9 N CH3 CY pKa 5 3' (Inactive) N 4'-N-Desmethylolanzapine (Active) 2'5' N HeterocyclicCH 2-Hydroxymethylolanzapine N 1' 3 N CH3 6 pKa 5 methylamino N(Inactive)CH3 5 3 N (Active)N 5' HeterocyclicN 5 7 1' 5 6 N CH3 6 N N CH3 N S 2 3 UG methylamino6 N N CH3 3 8 5 T2B 3 HO N 9 H 1 7 N 7 7 7 105 CH CH 10 CH5 N 3 2 3 2 N3 6 N S 1 Olanzapine8 N S UG8 N S6 H 3 T2B 1 3 HO 9 log p9 4.09H 1 97 gluc 7 7 7-Hydroxyolanzapine10 CH 10 CH 3 Olanzapine-10-glucuronide 2 3 N S 1 Olanzapine 8 N S (Active)H 1 9 log p 4.09 (Inactive)9 gluc 7-Hydroxyolanzapine FigureFigure 18.18. Metabolic pathways pathways of of olanzapine. olanzapine. Olanzapine-10-glucuronide (Active) (Inactive) 3.5.3.5. OlanzapineOlanzapine FigureOlanzapineOlanzapine 18. Metabolic (Figure pathways 18)18) is is a a second-generationof second-generation olanzapine. antipsychotic antipsychotic used used in the in thetreatment treatment of of schizophrenia,schizophrenia, bipolar bipolar disord disorderer [ref] [ref] and and for for treatment-resistant treatment-resistant depression. depression. The mecha- The mech- anism3.5.nism Olanzapine of of action action of of olanzapine olanzapine in inthe the manage managementment of schizophrenia of schizophrenia has been has proposed been proposed as asmediation mediationOlanzapine through through (Figurea combination a combination 18) is of a dopaminesecond-generation of dopamine and serotonin and serotoninantipsychotic type 2 (5HT2) type 2used antagonisms (5HT2) in the antago- treatment of [72]. Olanzapine contains a heterocyclic tertiary methylamino moiety and is metabolized nismsschizophrenia, [72]. Olanzapine bipolar contains disord aer heterocyclic [ref] and tertiaryfor treatment-resistant methylamino moiety depression. and is metab- The mecha- as shown in Figure 18 to active 2 and 7-hydroxy derivatives, N-demethylation to 4′-N- olizednism of as shownaction inof Figureolanzapine 18 to activein the 2 manage and 7-hydroxyment of derivatives, schizophreniaN-demethylation has been proposed to as 4desmethylolanzapine,0-N-desmethylolanzapine, glucuronidation glucuronidation at posi attion position 10 to olanzapine-10-glucuronide 10 to olanzapine-10-glucuronide and mediation through a combination of dopamine and serotonin type 2 (5HT2) antagonisms and4′-N 4-oxygenation0-N-oxygenation to olanzapine-oxide to olanzapine-oxide [72–76]. [72 –The76]. latter The latterthree metabolites three metabolites are reported are reported to to[72].lack lack pharmacologic Olanzapine pharmacologic containsactivity activity at athe heterocyclic at observed the observed concentrations tertiary concentrations methylamino [72]. The [72 pKa]. moiety Theand log pKa andp values and is log metabolized p valuesasof olanzapineshown of olanzapine in and Figure N-desmethylolanzapine and 18N to-desmethylolanzapine active 2 and are 7-hydroxy given are in Figure given derivatives, in18. Figure 18N.-demethylation to 4′-N- desmethylolanzapine, glucuronidation at position 10 to olanzapine-10-glucuronide and 4′-N-oxygenation to olanzapine-oxide [72–76]. The latter three metabolites are reported to lack pharmacologic activity at the observed concentrations [72]. The pKa and log p values of olanzapine and N-desmethylolanzapine are given in Figure 18.

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3.6. Ketamine

Molecules 2021, 26, 1917 Ketamine (Figure 19) is an N-methyl-D-aspartate (NMDA) receptor antagonist14 ofwith 40 a potent effect [77]. Ketamine is a chiral drug and exists as R and S enantiomers; the S-enantiomer is marketed under the name of for use as an anesthetic [78,79]. Ketamine contains a methylamino moiety bonded to a cyclohexanone moiety. It 3.6.is mainly Ketamine metabolized to active N-desmethylketamine (), which is further me- tabolizedKetamine by cyclohexanone (Figure 19) is an hydroxylationN-methyl-D-aspartate at positions (NMDA) 4, 5 and receptor 6 of the antagonist cyclohexanone with a potentring as anesthetic depicted effectin Figure [77]. 19 Ketamine [78–81]. isAll a chiralthe hydroxylated drug and exists norketamine as R and Smetabolitesenantiomers; are theinactiveS-enantiomer and are isfurther marketed metabolized under the in name phase of II esketamine to inactive for glucuronide use as an anesthetic conjugates [78 at,79 the]. Ketaminehydroxyl contains(OH) groups a methylamino [79]. 5-Hydroxynorke moiety bondedtamine to a is cyclohexanone further metabolized moiety. by It is dehydro- mainly metabolizedgenation to to5,6-, active N-desmethylketamine which (norketamine), is and active anesthetic which is furtherand has metabolized proved to be byof cyclohexanoneforensic significance hydroxylation because of at its positions long half-life 4, 5 [79]. and 6 of the cyclohexanone ring as depictedThe in pKa Figure and 19 log[ 78 p –values81]. All of the ketamine hydroxylated and norketamine norketamine are metabolites given in Figure are inactive 19. It is andto be are noted further that metabolized the pKa of ketamine in phase IIcorres to inactiveponding glucuronide to the secondary conjugates methylamino at the hydroxyl moiety (OH)is higher groups than [79 that]. 5- of norketamine, which iscorresponds further metabolized to the primary by dehydrogenation amino group (Fig- to 5,6-dehydronorketamine,ure 19). This is explained which by the is positive and active inductive anesthetic effect and of hasthe provedmethyl togroup be of increasing forensic significancethe electron because density ofon its the long nitrogen half-life with [79 the]. consequent increase in basicity.

pKa 7.27 H2N H2N log P 2.91 O O Cl Cl * 6 A4 P3 HO Methylamino- CY cyclohexanone Norketamine 6-Hydroxynorketamine (Active) H (Inactive) N 2 O 3 Cl H N 1 * H N 2 2 O 6 4 O Cl Cl 5 6 Ketamine H2N 6 5 O 5 pKa 7.45 log P 3.35 Cl OH 5,6-dehydro- 4 OH 5-Hydroxynorketamine norketamine (Inactive) (Active) * Chiral center 4-Hydroxynorketamine (Inactive) Figure 19. Metabolic pathways of ketamine. Figure 19. Metabolic pathways of ketamine.

3.7. TheChlorpromazine pKa and log p values of ketamine and norketamine are given in Figure 19. It is to beChlorpromazine noted that the (Figure pKa of 20) ketamine is the prototyp correspondinge of the to phenothiazin the secondarye class methylamino of antipsy- moietychotics/neuroleptics. is higher than thatIt produces of norketamine, its antipsycho whichtic corresponds effect by the to thepost-synaptic primary amino blockade group at (Figurethe dopamine 19). This D2 is explainedreceptors byin the positivemesolimbic inductive pathway effect of ofthe the methyl [82,83]. group Due increasing to its in- theteraction electron with density several on the sites nitrogen including with , the consequent , increase in basicity.adrenergic, and sero- tonergic receptors, chlorpromazine has indications as , major tranquilizer and 3.7.in the Chlorpromazine treatment of intractable , in addition to the side effects associated with those interactions..Chlorpromazine Chlorpromazine (Figure20 )contains is the prototype a dimethylaminopropylene of the moiety; class ofit antipsy-is mainly chotics/neuroleptics.metabolized through Itthe produces pathways its depicted antipsychotic in Figure effect 20 by[84–88]. the post-synaptic The pharmacologically blockade atactive the dopamine metabolites D2 of receptors chlorpromazine in the mesolimbic include promazine, pathway of N the-desmethylchlorpromazine, brain [82,83]. Due to its interactionand 7-hydroxychlorpromazines with several sites including [87]. The histaminergic, 5-sulfoxide cholinergic, and N-oxide adrenergic, metabolites and (Figure seroton- 20) ergicare pharmacologically receptors, chlorpromazine inactive [87]. has indicationsFurther, the as metabolism antiemetic, of major chlorpromazine tranquilizer involves and in thethe treatment 7-hydroxylation of intractable and 5-sulfoxidation hiccups, in addition of N-desmethylchlorpromazine to the side effects associated [87]. with The those 7-hy- interactions..droxy and N-desmethyl Chlorpromazine metabolites contains also a form dimethylaminopropylene glucuronide conjugates moiety; in phase it is II mainly [87]. metabolizedThe pKa through and log the p values pathways of chlorpromazine depicted in Figure are 20given[ 84– in88 Figure]. The pharmacologically20. No correspond- activeing values metabolites have been of chlorpromazine found for N-desmethylchlorpromazine; include promazine, N-desmethylchlorpromazine, however, the values can and be 7-hydroxychlorpromazinesestimated as being, respectively, [87]. The higher 5-sulfoxide and lower and thanN-oxide those metabolitesof chlorpromazine. (Figure 20) are pharmacologically inactive [87]. Further, the metabolism of chlorpromazine involves the 7-hydroxylation and 5-sulfoxidation of N-desmethylchlorpromazine [87]. The 7-hydroxy and N-desmethyl metabolites also form glucuronide conjugates in phase II [87]. The pKa and log p values of chlorpromazine are given in Figure 20. No corresponding values have been found for N-desmethylchlorpromazine; however, the values can be estimated as being, respectively, higher and lower than those of chlorpromazine. Molecules 2021, 26, x FOR PEER REVIEW 15 of 41

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Chlorpromazine S

Chlorpromazine R R R Cl SN CYP21A CYP21A R pKaR 9.2Cl N Dimethyl- R CYP21A NH log P 4.54 N aminoropyl CYP21A NH2 pKa 9.2 R Dimethyl- N,N-desmethylchlorpromazine NH log P 4.54 N aminoropylN-desmethylchlorpromazine NH2 R CY (Active) N,N-desmethylchlorpromazine N-desmethylchlorpromazineP2 N D6 4 6 O S OH CY (Active)3 P2 5 7 Glucuronide N D6 4 6 Chlorpromazine-N-oxideO S OH8 conjugate O Cl3 2 N Glucuronide (Inactive) 1 5 10 7 9 6 Chlorpromazine-N-oxide 4 S 8 conjugate O Cl 2 N 7-Hydroxychlorpromazine (Inactive) 3 5 7 1 10 9 4 6 S 8 N (Moderately active) Cl3 2 5 7-Hydroxychlorpromazine 1 10 79 8 N (Moderately active) Cl 2 S Chlorpromazine 5-sulfoxide1 10 9 3 5 6 7 S Chlorpromazine(Inactive) 5-sulfoxide N 3 2 5 6 7 8 1 10 9 Promazine (Inactive) N 2 8 1 10 9 Promazine(Active) N (Active) N Figure 20. Major metabolic pathways of chlorpromazine. FigureFigure 20. 20.Major Major metabolic metabolic pathwayspathways of chlorpromazine. 3.8. Promazine 3.8.3.8. Promazine Promazine Promazine (Figure 21) belongs to the phenothiazine class of antipsychotic/neurolep- tic classPromazinePromazine of drugs (Figure (Figure that act21 21)) at belongs belongs the D2 to todopamine thethe phenothiazinephenot receptorhiazine classclassin the ofof mesolimbic antipsychotic/neurolepticantipsychotic/neurolep- pathway of the classbraintic class of [82]. drugs of Itdrugs is that used that act in act atthe at the short-term the D2 D2 dopamine dopamine treatmentreceptor receptor of disturbed in the mesolimbic mesolimbic behavior. pathwayDue pathway to its of interac- ofthe the brain [82]. It is used in the short-term treatment of disturbed behavior. Due to its interac- braintion with [82]. the It is histamine-1 used in the receptor, short-term it is treatment also used ofas disturbedantiemetic behavior. [89]. Promazine Due to contains its inter- a tion with the histamine-1 receptor, it is also used as antiemetic [89]. Promazine contains a actiondimethylaminopropylene with the histamine-1 moiety receptor, and itis ismainly also used metabolized as antiemetic via the [ 89routes]. Promazine shown in con- Fig- tainsdimethylaminopropylene a dimethylaminopropylene moiety moietyand is mainly and is metabolized mainly metabolized via the routes via the shown routes in shownFig- ure 21 [88–95]. Despite a lack of literature reports on the pharmacologic activity of prom- inureFigure 21 [88–95]. 21 [88– Despite95]. Despite a lack aof lack literature of literature reports reportson the pharmacologic on the pharmacologic activity of activity prom- of azine metabolites, predictions can be made with reference to known cases: the N- promazineazine metabolites, metabolites, predictions predictions can canbe made be made with with reference reference to known to known cases: cases: the theN- N- desmethyl and 7-hydroxymetabolites have attenuated activities; the 5-sulfoxide metabo- desmethyldesmethyl and and 7-hydroxymetabolites 7-hydroxymetabolites have have attenuated attenuated activities; activities; the the 5-sulfoxide 5-sulfoxide metabolite metabo- is lite is devoid of activity. In a detailed study of promazine metabolism, Goldenberg et al. devoidlite is ofdevoid activity. of activity. In a detailed In a detailed study of stud promaziney of promazine metabolism, metabolism,Goldenberg Goldenberg et al. (1964) et al.[91 ] (1964) [91] reported the formation of 3-hydroxy-N-desmethylpromazine, 5-sulfoxide-N- reported(1964) [91] the reported formation the of formation 3-hydroxy- of N3-hydroxy--desmethylpromazine,N-desmethylpromazine, 5-sulfoxide- 5-sulfoxide-N- desmethyl-N- desmethylpromazine and glucuronide and sulfate conjugation of 3-hydroxypromazines promazinedesmethylpromazine and glucuronide and glucuronide and sulfate and conjugation sulfate conjugation of 3-hydroxypromazines of 3-hydroxypromazines (Figure 21 ). (Figure 21). The pKa and log p values of promazine and N-desmethylpromazine are given The(Figure pKa and21). The log ppKavalues and oflog promazine p values of andpromazineN-desmethylpromazine and N-desmethylpromazine are given inare Figure given 21. inin FigureFigure 21.21.

S PromazinePromazine

N RR N-desmethylpromazine RR CYP1A2CYP1A2 N-desmethylpromazine pKapKa 10.02 10.02 log log P 3.55 P 3.55 pKapKa 9.369.36 loglog PP 3.933.93 NN NHNH CCY Glucuronide YP2 Glucuronide PD26 Dimethylamino- D6 conjugatation Dimethylamino- C conjugatation propylene CY propylene YP P2 6 4 2D 6 S 4 OH D6 O 7 5 S OH 6 O 3 7 5 3 6 S 4 8 2 7 6 S 4 3 8 N 2 5 9 10N 1 7 5 3 10 8 2 9 1 N 3-Hydroxypromazine 8 9 10 1 2 3-Hydroxypromazine N10 (Active) 9 1 N (Active) Promazine 5-sulfoxide N Promazine 5-sulfoxide (Inactive) N (Inactive) N

Figure 21. Metabolic pathways of promazine. FigureFigure 21. 21.Metabolic Metabolic pathways pathways of of promazine. promazine.

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4. Histamine-1 Receptor Inverse Antagonists 4. Histamine-1 Receptor Inverse Antagonists The first-generation H1-anithistamines are characterized by the presence of a diaryl- ring systemThe first-generation and a dimethylamino H1-anithistamines moiety bridged are characterized by a 2-3 carbonby the presence chain. The of a protonated diaryl- aminoring system group and and a thedimethylamino diaryl-ring moiety system bridged represent by thea 2-3 primary carbon chain. The protonated in the first-generationamino group and H1-antihistamines the diaryl-ring system [96]. Having represent a pKa the of primary ~9, the aminopharmacophores group interacts in the with thefirst-generation H1-histamine H1-antihistamines receptor via ion-ionic [96]. Having or hydrogen a pKa bond of ~9, bindings the amino while group the interacts diaryl-ring systemwith the interacts H1-histamine with the receptor receptor via ion-ionic via hydrophobic or hydrogen binding bond [ 96bindings]. As depicted while the in diaryl- Figure2, thering protonated system interacts amino with nitrogen the receptor provides via the hydrophobic ion in the H1- binding [96]. As depicted while the in receptor Fig- providesure 2, the the protonated aspartate amino amino-acid nitrogen residue provides that containsthe ion in the the negatively H1-antihistamine charged while carboxylate the receptor provides the aspartate amino-acid residue that contains the negatively charged group (COO−) needed for the ion-ion binding interaction. Furthermore, the receptor carboxylate group (COO-) needed for the ion-ion binding interaction. Furthermore, the provides the hydrogen-containing groups involved in hydrogen bonding, mostly the OH receptor provides the hydrogen-containing groups involved in hydrogen bonding, mostly group in or . the OH group in serine or glutamine. 4.1. Diphenhydramine 4.1. Diphenhydramine Diphenhydramine (Figure 22), of the ethanolamine chemical class, is taken to rep- Diphenhydramine (Figure 22), of the ethanolamine chemical class, is taken to repre- resent the first-generation H1-antinistamines. Diphenhydramine is metabolized as per sent the first-generation H1-antinistamines. Diphenhydramine is metabolized as per the the pathways shown in Figure 22[ 96,97]. According to Foye (2013) [98], “N-desmethyl pathways shown in Figure 22 [96,97]. According to Foye (2013) [98], “N-desmethyl and and N,N-didesmethyl metabolites contribute very little to the observed antihistaminic N,N-didesmethyl metabolites contribute very little to the observed antihistaminic proper- properties of diphenhydramine”. On the other hand, the acetamide and the carboxylic- ties of diphenhydramine’’. On the other hand, the acetamide and the carboxylic-acid me- acidtabolites metabolites (Figure 22) (Figure lack the22) pharmacophoric lack the pharmacophoric amino group amino and are group therefore and aredevoid therefore of devoidH1-antihistaminic of H1-antihistaminic activity. The activity. pKa Theand pKalog andp values log p valuesof diphenhydramine of diphenhydramine and N- and Ndesmethyldiphenhydramine-desmethyldiphenhydramine are aregiven given in Figure in Figure 22. 22.

pKa 9.68 log P 3.09 H CYP2D6 N Dimethylaminoethyl O NH2 O D6 30% P2 Y A2 C P1 N-Desmethyldi- CY N,N-Didesmethyl- C9 phenhydramine P2 9 diphenhydramine CY C1 (Less active than 13% P2 N CY diphenhydramine) (Little antihistamine O activity)

Diphenhydramine H N OCOOH pKa 8.98 O COCH3 log P 3.27 N-Acetyl-N-desmethyl- Diphenylmethoxyacetic acid diphenhydramine (Inactive) (Inactive)

FigureFigure 22.22. MetabolicMetabolic pathways of of diphenhydramine. diphenhydramine.

4.2.4.2. AzelastineAzelastine AzelastineAzelastine (Figure(Figure 2323),), aa phthalazinephthalazine derivative,derivative, isis aa second-generationH1-antihistaminesecond-generationH1-antihista- andmine mast and cellmast stabilizer. cell stabilizer. It contains It contains a heterocyclic a heterocyclic tertiary tertiary methylamino methylamino moiety moiety and and is me- tabolizedis metabolized by oxidative by oxidativeN-demethylation N-demethylation by the by cytochrome the enzymesP450 enzymes to the to principal the activeprincipal product activeN product-desmethylazelastine, N-desmethylazelastine, which has which H1-receptor has H1-receptor antagonistic antagonistic activity ac- with longertivity with duration longer of duration action than of action the parent than the drug parent [99 –drug103]. [99–103]. The pKa The and pKa log andp values log p of azelastinevalues of azelastine and N-desmethylazelastine and N-desmethylazelastine are given ar ine given Figure in 23 Figure. 23.

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H N O N O CYP3A4 N CYP3A4 N CYP2D6 Heterocyclic tertiary N N methylamino CYP1A2

Cl Cl Azelastine N-Desmethylazelastine pKa 9.19 log P 1.34 (Active) FigureFigure 23.23. MetabolismMetabolism ofof azelastine.azelastine.

4.3.4.3. PromethazinePromethazine PromethazinePromethazine (Figure(Figure 24 24)) isis aa phenothiazinephenothiazine derivative. derivative. TheThe introductionintroduction of of aa methylmethyl branchbranch inin thethe alkylalkyl chainchain ofof antipsychoticantipsychotic ,phenothiazines, suchsuch asas promazinepromazine andand chlor-chlor- promazinepromazine (Figure(Figure 2424),), has introduced introduced a a detour detour in in the the mechanism mechanism of of action action of ofprometha- promet- hazinezine [104]. [104 With]. With such such structural structural modificati modification,on, promethazine belongs belongs to the to thetricyclic tricyclic H1- H1-antihistaminesantihistamines and and is used is used to treat to treat allergic allergic reactions reactions as well as wellas as nausea and andemesis. emesis. Pro- Promethazinemethazine contains contains a dimethylaminoisopropyl a dimethylaminoisopropyl moiety moiety and and is metabolized is metabolized by CYP2D6 by CYP2D6 iso- isozymezyme via via the the pathways pathways shown shown in Figure in Figure 24 [104–110].24[ 104–110 The]. ThepKa pKa and andlog p log valuesvaluesp values ofof pro-pro- of promethazinemethazine and and N-desmethylpromethazineN-desmethylpromethazine are are given given in Figure in Figure 24. 24 .

Dimethylamino- R S isopropylisopropyl CYP2D6 R R N N CYP2D6 pKa 9.62 Promethazine O NH loglog PP 3.903.90

Promethazone-N-oxide pKa 9.1 N

C

C CY N-Desmethylpromethazine

Y

(Inactive) loglog PP 4.814.81 Y P2 P

P D

2

2 6

D D O 6

6 6 4 6 4 6 S HO S 4 7 HO S 5 3 7 5 3 7 5 3 8 1 2 8 1 2 1 N N 8 2 9 10 N 10 10 9 9 H

N10-desalkylpromethazine N N

Promethazine 5-sulfoxide 7-Hydroxypromethazine (Inactive) (Active) FigureFigure 24.24. MetabolicMetabolic pathwayspathways ofof promethazine.promethazine.

5.5. Opioid-muOpioid-mu ReceptorReceptor AgonistsAgonists AlkylaminoAlkylamino moieties (open (open chain chain aliphatic aliphatic or or heterocyclic) heterocyclic) feature feature in insome some mu-re- mu- receptorceptor agonists; agonists; they they are are metabolized metabolized by by oxidative oxidative dealkylation by CYP450CYP450 isozymesisozymes toto NN-desalkylamino-desalkylamino products.products. 5.1. Morphine and Codeine 5.1. Morphine and Codeine A heterocyclic tertiary methylamino moiety is a common structural feature of mor- A heterocyclic tertiary methylamino moiety isis aa commoncommon structuralstructural featurefeature ofof mor-mor- phine and codeine (Figure 25) and other semisynthetic narcotic analgesics. In phine and codeine (Figure 25) and other semisynthetic opiate narcotic analgesics. In mor- morphine and codeine, this group is subject to metabolic N-demethylation to normor- phine and codeine, this group is subject to metabolic N-demethylation to phine and , respectively. Normorphine is only 25% as active as as and norcodeine, respectively. Normorphine is only 25% as active as analgesic as morphine morphine [111]. According to DeRuiter [112], the decrease in the analgesic activity of [111]. According to DeRuiter [112], the decrease in the analgesic activity of normorphine normorphine compared to morphine is due to increased polarity with the consequent compared to morphine is due to increased polarity with the consequent reduction in reduction in -brain barrier crossing. The same reasoning may be extrapolated to blood-brain barrier crossing. The same reasoning may be extrapolated to norcodeine re- norcodeine reduced pharmacologic activity in comparison to codeine. The main route duced pharmacologic activity in comparison to codeine. The main route of morphine me- ofduced morphine pharmacologic metabolism activity is glucuronidation in comparison to at codeine. positions The 3 andmain 6 route (Figure of morphine25)[113–116 me-], tabolism is glucuronidation at positions 3 and 6 (Figure 25) [113–116], with morphine-6-

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with morphine-6-glucuronide accounting for the major part of analgesic activity of mor- phineglucuronideglucuronide [112]. accounting In addition for to theO-demethylation major part of an toalgesic morphine, activityactivity codeine ofof morphinemorphine is metabolized [112].[112]. InIn ad-ad- in a similarditiondition toto manner OO-demethylation-demethylation to morphine to morphine, (Figure 25 ),codeine with the isis metabolizedmetabolized 6-glucuronide inin aa conjugate similarsimilar mannermanner playing toto the morphine (Figure 25), with the 6-glucuronide conjugate playing the major role in analge- majormorphine role (Figure in analgesia 25), with and the norcodeine 6-glucuronide playing conjugate only a playing little role the [117 major]. The role pKa in analge- and log p sia and norcodeine playing only a little role [117]. The pKa and log p values of codeine valuessia and of norcodeine codeine and playing morphine only anda little their roleN -desmethyl[117]. The pKa metabolites and log p are values given of in codeine Figure 25. andand morphinemorphine and their N-desmethyl metabolites areare givengiven inin FigureFigure 25.25.

NCH3 NCH3 Heterocyclic tertiary methylmino pKa 9.77 methylmino pKa 9.77 pKa 9.12 NCH NH Morphine NCH3 gluc-O 3 O OH NH Morphine 3 gluc-O 3 O OH Normorphine Normorphine 1 8 Morphine-3-glucuronide Minor 1 8 Morphine-3-glucuronide Minor 2 NCH3 2 7 UGT2B7 (70%) NCH3 (2.5%) 7 UGT2B7 (70%) (2.5%) 34 5 6 pKa 9.12 HO O OH HO 34O 5 6OH pKa 9.12 HO O OH HO O OH pKa 2.87 pKa 10.26 pKa 2.87 pKa 10.47 pKa 10.26 pKa 10.47 log P 0.9 HO O 6 O-gluc log P 0.9 HO O 6 O-gluc CYP2D6 pKa 9.2 CYP2D6 pKa 9.19 Morphine-6-glucuronide pKa 9.2 pKa 9.19 Morphine-6-glucuronide

NH NCH3 log P -3 NCH3 NH NCH3 log P -3 NCH3 pKa 9.19 1 8 pKa 9.19 Minor 1 8 UGT2B7 Minor 2 7 UGT2B7 pKa 2.87 2 7 (80%) pKa 2.87 6 6 H CO O OH H CO 3 4 O 5 OH (80%) H CO O O-gluc 3 3 4 O 5 6 3 O 6 H3CO O OH H3CO 3 OH H3CO O-gluc Norcodeine Codeine Codeine-6-glucuronide Norcodeine Codeine Codeine-6-glucuronide log P 0.89 log P 1.34 log P 0.89 log P -2.8 log P 1.34 log P -2.8 Figure 25. Metabolic pathways of codeine and morphine. FigureFigure 25. Metabolic pathways pathways of of codeine codeine and and morphine. morphine. 5.2.5.2. TramadolTramadol 5.2. Tramadol TramadolTramadol (Figure (Figure 26) 26 )is isa centrally a centrally acting acting analgesic analgesic that exerts that exerts its effect its through effect through two Tramadol (Figure 26) is a centrally acting analgesic that exerts its effect through two twomechanisms: mechanisms: (a) as (a) neurotransmitter as neurotransmitter reuptake reuptake inhibitor, inhibitor, and (b) and as mu-receptor (b) as mu-receptor ag- mechanisms: (a) as neurotransmitter reuptake inhibitor, and (b) as mu-receptor agonist onist[118]. [ 118It is]. of It interest is of interest to note to that note tramadol that tramadol has been has designed been designed as a congener as a congener of the mu- of the [118]. It is of interest to note that tramadol has been designed as a congener of the mu- mu-receptorreceptor agonist agonist codeine codeine [119]. [119 Tramadol]. Tramadol contains contains an aromatic an aromatic methoxy methoxy group groupand an and al- an receptor agonist codeine [119]. Tramadol contains an aromatic methoxy group and an al- aliphaticiphatic dimethylaminomethyl dimethylaminomethyl group. group. The The major major pathways pathways of tramadol of tramadol metabolism metabolism are are iphatic dimethylaminomethyl group. The major pathways of tramadol metabolism are depicteddepicted inin FigureFigure 26 [[120–122].120–122]. OO-desmethyltramadol-desmethyltramadol is isthe the major major active active metabolite metabolite of of depicted in Figure 26 [120–122]. O-desmethyltramadol is the major active metabolite of tramadol;tramadol; itit actsacts mainly as as mu-receptor mu-receptor agonist agonist [122]. [122 ].On On the the other other hand, hand, the the N-desmethylN-desmethyl tramadol; it acts mainly as mu-receptor agonist [122]. On the other hand, the N-desmethyl metabolite (nortramadol) is devoid of analgesic activity [122]. The pKa and log p values metabolitemetabolite (nortramadol)(nortramadol) is devoid of analgesic activity [122]. [122]. The The pKa pKa and and log log pp valuesvalues of of tramadol and nortramadol are given in Figure 26. tramadolof tramadol and and nortramadol nortramadol are are given given in in Figure Figure 26 26.. H H N pKa 9.89 N CH pKa 9.89 Dimethylaminomethyl H3CO 3 log P 2.07 H CO CH3 Dimethylaminomethyl 3 log P 2.07 H * C H CH3 Y N * C P2 N CH3 4 Y D HO CH3 N 3A HO P2 6 YP 4 HO D6 HO CH3 H CO N CH3 C 3A 6 3 YP 2B Nortramadol CH3 C P 6 * H3CO CY 2B Nortramadol YP (inactive) * * C (inactive) HO * CH3 HO HO CY P2 N CH3 O-desmethylnortramadol HO CY D 4 P 6 A O-(Lessdesmethylnortramadol active than Tramadol 2D HO N CH3 3 4 6 P A Tramadol HO CH3 Y 3 tramadol(Less active as analgesic) than pKa 9.23 C P Y tramadol as analgesic) pKa 9.23 * C log P 2.45 * log P 2.45 HO HO O-Desmethyltramadol * Chiral center O-Desmethyltramadol Glucuronnide conjugation * Chiral center (200 as active as tramadol atGlucuronnide phenolic OH conjugation (200as mu-receptor as active as agonist) tramadol at phenolic OH as mu-receptor agonist) Figure 26. Metabolic pathways of tramadol. FigureFigure 26. Metabolic pathways pathways of of tramadol. tramadol.

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5.3.5.3. 5.3.Propoxyphene PropoxyphenePropoxyphene PropoxyphenePropoxyphenePropoxyphene (Figure (Figure (Figure 27) 27 )27)is is a a is chiral a chiral drugdrug drug whose whose whose dextro dextro dextro enantiomer enantiomer enantiomer () (dextropropox- (dextropropox- yphene)isyphene) an opioidis an is opioid an mu-receptor opioid mu-receptor mu-receptor agonist agonist usedagonist used as anused as analgesic an as analgesican analgesic in the in the treatment in thetreatment treatment of mildof mild of to mild mod-to to moderateeratemoderate pain pain pain [ 123[123]. ].[123]. It contains It contains a a dimethylaminopropyl dimethylaminopropyl a dimethylaminopropyl moiety moiety moiety (Figure (Figure (Figure 27). 27 27). ).The The The major majormajor routerouteroute of ofmetabolismof metabolismmetabolism of ofdextropropoxypheneof dextropropoxyphenedextropropoxyphene is isNis-demethylationN N-demethylation-demethylation to tonorpropoxypheneto norpropoxyphenenorpropoxyphene (Figure((FigureFigure 27) 27 27)[123,124],)[ 123[123,124],,124 which], which which is active is is active active as a as as mu-receptor aa mu-receptormu-receptor agonist agonistagonist and andand is used isis usedused clinically. clinically.clinically. Dex- Dex-Dex- tropropoxyphenetropropoxyphenetropropoxyphene has hashasbeen been chosen chosen chosen as an as as example an an example example where where where metabolic metabolic metabolic N-dealkylation N-dealkylationN-dealkylation has hasled has led to theledto theformation to theformation formation of a of cardiotoxic a of cardiotoxic a cardiotoxic metabolite metabolite metabolite with with the with theconsequent consequent the consequent withdrawal withdrawal withdrawal of the of thedrug of drug the in thedrugin theUS in USand the and Europe US Europe and with Europe with restricted restricted with restricted use usein other in use other countries in othercountries countries[125]. [125]. It is [It 125interesting is ].interesting It is interesting to note to note thattothat despite note despite that the despitethepresence presence the of presencean of an ester group of angroup esterand and two group two unhindered andunhindered two phenyl unhindered phenyl groups groups phenyl in dextro- in groups dextro- propoxyphene,inpropoxyphene, dextropropoxyphene, ester ester hydrolysis hydrolysis ester and hydrolysis and aromatic-r aromatic-r anding aromatic-ring inghydroxylation hydroxylation hydroxylation have have not notbeen have been reported not reported been as metabolicreportedas metabolic as pathways metabolic pathways of pathways this of this drug. drug. of The this The pKa drug. pKa and Theand log pKa logp values p and values logof propoxyphene pofvalues propoxyphene of propoxyphene and and nor- nor- propoxypheneandpropoxyphene are aregiven given in are Figure in given Figure 27. in Figure27. 27.

DimethylaminopropylDimethylaminopropyl

O O O O O OO O H H * *N N * N N CYP3A4CYP3A4 * * * * * (25%)(25%) pKa pKa10.17 10.17 log Plog 4.52 P 4.52 PrpoxyphenePrpoxyphene NorpropoxypheneNorpropoxyphene pKa pKa= 9.52 = 9.52 log P log = 4.9P = 4.9 (cardiotoxic)(cardiotoxic) FigureFigureFigure 27. 27.Major27.Major Major metabolic metabolicmetabolic pathway pathwaypathway of dextropropoxyphene. ofof dextropropoxyphene.dextropropoxyphene.

5.4.5.4. 5.4.Meperidine MeperidineMeperidine () (Pethidine)(Pethidine) MeperidineMeperidineMeperidine (Figure (Figure (Figure 28) 28 is28)) an is is anopioid an opioidopioid mu-recep mu-receptor mu-receptor agonisttor agonist agonist used used used as analgesic. as as analgesic. analgesic. It contains It It contains contains a heterocyclicaa heterocyclicheterocyclic tertiary tertiary tertiary methylamino methylamino methylamino moiety moiety moiety (Figure (Figure (Figure 25). 25 ).25). The The The metabolic metabolic metabolic pathways pathways ofof meperi-me- of me- peridinedineperidine are are givenaregiven given inin Figure in Figure 28 [[126,127]. 28126 [126,127].,127]. Normep Normeperidine Normeperidineeridine is is as asis half as half half as as potent as potent potent as asmeperidine as meperidine meperidine butbut buttwice twicetwice as active as active as CNS as as CNS CNS stimulant stimulant [106]. [106]. [106 Further,]. Further, Further, neurotoxicity neurotoxicity has hasled has ledto ledrestricted to restricted to restricted use use of usenormeperidineof normeperidine of normeperidine as anas asopioidan anopioid opioid analgesic analgesic analgesic [128]. [128]. [ 128It ].is It It noteworthyis is noteworthy that thatthat meperidine meperidinemeperidine and andand normeperidinenormeperidinenormeperidine are arealso also metabolized metabolized metabolized by ester by by ester esterhydrolysis hy hydrolysisdrolysis to the to tothecorresponding the corresponding corresponding inactive inactive inactive me- me- peridinemeperidineperidine acids acids [127]. acids [127]. The [127 The pKa]. The pKa and pKa and log and logp values p log valuesp ofvalues meperidine of meperidine of meperidine and and normeperidine normeperidine and normeperidine are givenare given are in Figuregivenin Figure in28. Figure 28. 28.

NorpmeperidineNorpmeperidine H H H H pKapKa 9.33 9.33log Plog 2.07 P 2.07 (Active)(Active) HeterocyclicHeterocyclic tertiary tertiary D6 D6 methylaminomethylamino 2 2 COOCCOOC2H5 2H5 YP YP C C 4 4 H H 3A 3A N N N N YP YP 9 9 LC L C C C1 C1 E CE P2 P2 MeperidineMeperidine CY CY N N pKa 8.59 log Plog 2.72 P 2.72 LC L COOHCOOH pKa 8.59 COOCCOOC2H5 2H5 E CE

COOHCOOH NormeperidinicNormeperidinic acid acid (Inactive)(Inactive) LCE: Liver carboxyesterase LCE: Liver carboxyesterase MeperidinicMeperidinic acid acid (Inactive)(Inactive) FigureFigureFigure 28. 28.Metabolic28.Metabolic Metabolic pathways pathwayspathways of meperidine ofof meperidinemeperidine (pethidine). (pethidine).(pethidine).

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6. Blockers 6.1.6. Calcium Verapamil Channel Blockers 6.1. VerapamilVerapamil (Figure 29) is a phenylalkylamine calcium- used in the treat- mentVerapamil of , (Figure angina29) is a andphenylalkylamine cardiac calcium-channel [129]. It containsblocker used an internal in the tertiary methylaminotreatment of hypertension, moiety (Figure angina 29 and). The cardiac metabolic arrhythmias pathways [129]. ofIt contains verapamil an internal are depicted in Figuretertiary 29methylamino[ 129–133]. moiety (Figure 29). retains The metabolic 20% of cardiovascularpathways of verapamil activity are of de- the parent drugpicted [134 in Figure]. On the29 [129–133]. other hand, NorverapamilN-desalkyl retains verapamil 20% of (D617) cardiovascular is presumably activity inactive of the due to parent drug [134]. On the other hand, N-desalkyl verapamil (D617) is presumably inactive the loss of a substantial (pharmacophoric) part of the molecule in the parent drug. The pKa due to the loss of a substantial (pharmacophoric) part of the molecule in the parent drug. and log p values of verapamil and norverapamil are given in Figure 29. The pKa and log p values of verapamil and norverapamil are given in Figure 29.

Tertiary methylamino CH H 3 CN CN CYP2C8 H CO NCH* H3CO NCH3 3 3 CYP3A4

CYP3A5 H CO H3CO 3 OCH3 R/S-Verapamil OCH3 pKa (9.68) OCH3 OCH3 C Norverapamil C Y log P 5.04 P CYP2D6 Y 2 C P C pKa 10.29 log P 4.66 3 Y A 8 P 3 4 (20% activity of verapamil as Inactive O-desmethyl A 2 calcium-channel blocker) metabolites H H3CO N

H3CO N-Desalkylverapamil (D617) Figure 29. Metabolic pathways of verapamil. Figure 29. Metabolic pathways of verapamil.

6.2.6.2. Diltiazem Diltiazem (Figure (Figure 30) 30 is) isa abenzothiazepine benzothiazepine calcium-channel calcium-channel blocker blocker with withantihyper- antihyperten- tensive and antiarrhythmic properties. It contains a dimethylaminoethyl moiety (Figure sive and antiarrhythmic properties. It contains a dimethylaminoethyl moiety (Figure 30) 30) and is primarily metabolized via the pathways shown in Figure 30 [134–136]. The four and is primarily metabolized via the pathways shown in Figure 30[ 134–136]. The four metabolites retain calcium channel blocking activity to varying extents, though less than metabolitesthe parent drug retain [135]. calcium The pKa channel and log blocking p values activityof diltiazem to varying and N-desmethyldiltiazem extents, though less than Molecules 2021, 26, x FOR PEER REVIEWtheare parentgiven in drug Figure [135 30.]. The pKa and log p values of diltiazem and N-desmethyldiltiazem21 of 41 are given in Figure 30.

OCH3

S N-desmethyldiltiazem * * O pKa 9.2 log P 2.34 N 4 O 3A O E P st CY er ase HN s OCH OH 3 OCH3

S S CYP2D6 O-desmethyl- S * * * * O * O diltiazem * OH N N N O O O O O E ste N ras N Desacetyl-N- Dimethyl- es OCH3 HN A4 desmethyldiltiazem aminoethyl P3 CY Diltiazem S * All metabolites retain calcium-channel pKa 8.06 log P 2.70 * OH blocking activity to varying extents. N O * Chiral carbon N Deacetyldiltiazem

FigureFigure 30. 30. MetabolicMetabolic pathways pathways of diltiazem. of diltiazem.

6.3. Amiodarone Amiodarone (Figure 31) is an antiarrhythmic drug used in the treatment of irregular heartbeats. It acts as a calcium-, potassium-, and -channel blocker [137,138]. It con- tains a diethylaminoethyl moiety and is metabolized as shown in Figure 31 by CYP3A4 and CYP2C8 N-demethylation to N-desethylamiodarone, which is active as antiarrhyth- mic [139–141]. The pKa and log p values of amiodarone and N-desethylamiodarone are given in Figure 31.

Diethylaminoethyl

O O I I O O CYP3A4 H N N O CYP2C8 O I I

Amiodarone N-Desethylamiodarone pKa 8.47 pKa 9.49 log P 6.9 log P 7.6a (Active) Figure 31. Metabolism of amiodarone.

7. Drugs Acting on Sodium Channels 7.1. Local Anesthetics Local anesthetics produce anesthesia by inhibiting excitation of nerve endings or by blocking conduction in peripheral nerves [142]. binds to the intracellular sur- face of sodium channels, which blocks the subsequent influx of sodium into the cell. Ac- tion potential propagation and nerve function is, therefore, prevented. This block is re- versible and when the drug diffuses away from the cell, function is re- stored and nerve propagation returns [143].

Molecules 2021, 26, x FOR PEER REVIEW 21 of 41

OCH3

S N-desmethyldiltiazem * * O pKa 9.2 log P 2.34 N 4 O 3A O E P st CY er ase HN s OCH OH 3 OCH3

S S CYP2D6 O-desmethyl- S * * * * O * O diltiazem * OH N N N O O O O O E ste N ras N Desacetyl-N- Dimethyl- es OCH3 HN A4 desmethyldiltiazem aminoethyl P3 CY Diltiazem S * All metabolites retain calcium-channel pKa 8.06 log P 2.70 * OH blocking activity to varying extents. N O * Chiral carbon Molecules 2021, 26, 1917 21 of 40 N Deacetyldiltiazem

Figure 30. Metabolic pathways of diltiazem. 6.3. Amiodarone 6.3. Amiodarone Amiodarone (Figure 31) is an antiarrhythmic drug used in the treatment of irregular heartbeats.Amiodarone It acts (Figure as a calcium-, 31) is an potassium-, antiarrhythmic and sodium-channeldrug used in the treatment blocker [137 of ,irregular138]. It containsheartbeats. a diethylaminoethyl It acts as a calcium-, moiety potassium- and is metabolized, and sodium-channel as shown inblocker Figure [137,138]. 31 by CYP3A4 It con- andtains CYP2C8 a diethylaminoethylN-demethylation moiety to N and-desethylamiodarone, is metabolized as shown which in is activeFigure as 31 antiarrhyth- by CYP3A4 micand [ 139CYP2C8–141]. N The-demethylation pKa and log top valuesN-desethylamiodarone, of amiodarone and whichN-desethylamiodarone is active as antiarrhyth- are givenmic [139–141]. in Figure 31The. pKa and log p values of amiodarone and N-desethylamiodarone are given in Figure 31.

Diethylaminoethyl

O O I I O O CYP3A4 H N N O CYP2C8 O I I

Amiodarone N-Desethylamiodarone pKa 8.47 pKa 9.49 log P 6.9 log P 7.6a (Active)

FigureFigure 31. 31.Metabolism Metabolism of of amiodarone. amiodarone.

7.7. Drugs Drugs Acting Acting on on Sodium Sodium Channels Channels 7.1.7.1. Local Local Anesthetics Anesthetics LocalLocal anesthetics anesthetics produce produce anesthesia anesthesia by by inhibiting inhibiting excitation excitation of of nerve nerve endings endings or or by by blockingblocking conduction conduction in in peripheral peripheral nerves nerves [142 [142].]. Prilocaine Prilocai bindsne binds to the to intracellularthe intracellular surface sur- offace sodium of sodium channels, channels, which which blocks blocks the subsequent the subsequent influx influx of sodium of sodium into theinto cell. the cell. Action Ac- potentialtion potential propagation propagation and nerve and functionnerve function is, therefore, is, therefore, prevented. prevented. This block This is block reversible is re- andversible when and the when drug diffusesthe drug away diffuses from away the cell, from sodium the cell, channel sodium function channel is function restored andis re- nervestored propagation and nerve propagation returns [143 ].returns [143]. Molecules 2021, 26, x FOR PEER REVIEW 22 of 41

7.1.1. Lidocaine Lidocaine (Figure 32) is a antiarrhythmic drug. As a local anesthetic, it belongs7.1.1. Lidocaine to the amino-amide class. Due to the steric protective effect provided by the two orthoLidocaine-methyl groups(Figure 32) on theis a local anesthetic ring, antiarrhythmic possible amide drug. hydrolysis As a local of anesthetic, lidocaine is excluded it belongs to the amino-amide class. Due to the steric protective effect provided by the two leaving only N-deethylation as the viable major metabolic route. The metabolic products ortho-methyl groups on the benzene ring, possible amide hydrolysis of lidocaine is ex- ofcluded lidocaine leaving are only monoethylglycinexylidide N-deethylation as the viable major (MEGX), metabolic which route. is activeThe metabolic as local anesthetic withproducts a longer of lidocaine duration are monoethylglycinexylidide of action than lidocaine, (MEGX), and which glycinexylidide is active as local and an- lidocaine-N- oxide,esthetic which with a longer are inactive duration (Figure of action 32 th)[an144 lidocaine,–147]. and The glycinexylidide pKa and log andp values lidocaine- of lidocaine and monoethylglycinexylideN-oxide, which are inactive (Figure are given 32) [144–147]. in Figure The32. pKa and log p values of lidocaine and monoethylglycinexylide are given in Figure 32.

N Diethylaminomethyl Lidocaine N O pKa 7.7 R log P 2.84 CYP3A4

R CYP3A4 N R NH N N 2 H O O Glycinexylidide Monoethylglycinexylidie (inactive) Lidocaine-N-oxide (MEGX) (active)

pKa 8.05 log P 1.32

FigureFigure 32. 32. MajorMajor metabolic metabolic pathways pathways of lidocaine. of lidocaine.

8. Drugs That Act on GABAAnergic Receptor 8.1. Zopiclone Zopiclone (Figure 33) is a cyclopyrrolone derivative with effects. Its mech- anism of action involves increase in the normal transmission of GABA in the CNS via modulating receptors in the same way that benzodiazepine drugs do [148]. Zopiclone contains a heterocyclic tertiary methylamino moiety (Figure 33). It is me- tabolized as per the pathways depicted in Figure 33 to give N-desmethylzopiclone, which is as active as hypnotic as zopiclone and zopiclone-N-oxide, which is devoid of hypnotic activity [149–153]. The pKa and log p values of zopiclone and N-desmethylzopiclone are given in Figure 33.

O O O N N N N N N N Cl N Cl N Cl N N N O O O O O CYP2E1 O CYP3A4 H H H

N N N H O Heterocyclic tertiary N-Desmethylzopiclone Zopiclone-N-Oxide Zopiclone methylamino pKa 7.81 log P 0.42 (Inactive) pKa 6.89 log P 0.81 (Active) Figure 33. Metabolic pathways of zopiclone.

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7.1.1. Lidocaine Lidocaine (Figure 32) is a local anesthetic antiarrhythmic drug. As a local anesthetic, it belongs to the amino-amide class. Due to the steric protective effect provided by the two ortho-methyl groups on the benzene ring, possible amide hydrolysis of lidocaine is ex- cluded leaving only N-deethylation as the viable major metabolic route. The metabolic products of lidocaine are monoethylglycinexylidide (MEGX), which is active as local an- esthetic with a longer duration of action than lidocaine, and glycinexylidide and lidocaine- N-oxide, which are inactive (Figure 32) [144–147]. The pKa and log p values of lidocaine and monoethylglycinexylide are given in Figure 32.

N Diethylaminomethyl Lidocaine N O pKa 7.7 R log P 2.84 CYP3A4

R CYP3A4 N R NH N N 2 H O O Glycinexylidide Monoethylglycinexylidie (inactive) Lidocaine-N-oxide (MEGX) (active)

Molecules 2021, 26, 1917 pKa 8.05 log P 1.32 22 of 40

Figure 32. Major metabolic pathways of lidocaine.

8.8. DrugsDrugs ThatThat ActAct onon GABAGABAAAnergicnergic ReceptorReceptor 8.1.8.1. ZopicloneZopiclone ZopicloneZopiclone (Figure(Figure 33 33)) isis aa cyclopyrrolonecyclopyrrolone derivativederivative withwith hypnotichypnotic effects.effects. ItsIts mech-mech- anismanism ofof actionaction involvesinvolves increaseincrease inin thethe normalnormal transmissiontransmission ofof GABAGABA inin thethe CNSCNS viavia modulatingmodulating benzodiazepine benzodiazepine receptors receptors in thein the same same way way that benzodiazepinethat benzodiazepine drugs drugs do [148 do]. Zopiclone[148]. Zopiclone contains contains a heterocyclic a heterocyclic tertiary tertiary methylamino methylamino moiety moiety (Figure (Figure 33). It 33). is metabo- It is me- lizedtabolized as per as the per pathways the pathways depicted depicted in Figure in Figure 33 to 33 give to giveN-desmethylzopiclone, N-desmethylzopiclone, which which is asis activeas active as as hypnotic hypnotic as as zopiclone zopiclone and and zopiclone- zopiclone-NN-oxide,-oxide, which which is is devoid devoid of of hypnotic hypnotic p N activityactivity [[149–153].149–153]. TheThe pKapKa andand loglog pvalues values of of zopiclone zopiclone and and N-desmethylzopiclone-desmethylzopiclone are are given in Figure 33. given in Figure 33.

O O O N N N N N N N Cl N Cl N Cl N N N O O O O O CYP2E1 O CYP3A4 H H H

N N N H O Heterocyclic tertiary N-Desmethylzopiclone Zopiclone-N-Oxide Zopiclone methylamino pKa 7.81 log P 0.42 (Inactive) pKa 6.89 log P 0.81 (Active) Figure 33. Metabolic pathways of zopiclone. Figure 33. Metabolic pathways of zopiclone.

9. Muscarinic Receptor Blockers 9.1. Tolterodine/Fesoterodine Tolterodine (Figure 34) is an antimuscarinic drug used in the treatment of (OAB) and urinary urge incontinence. It contains a diisopropylaminopropyl moiety. As shown in Figure 34, tolterodine is metabolized through monodeisopropylation to give an inactive metabolite and through benzylic-methyl group oxidation to give 5-hydroxymethyl

tolterodine (5-HMT), which is equiactive with the parent drug [154–157]. Despite being equiactive to its parent drug, 5-HMT did not qualify to the status of metabolite drug because of its high hydrophilicity (log p value of 0.73) and, accordingly, poor [155]. However, the problem has been resolved by esterifying the aromatic hydroxy (phenolic) group with isobutanoic acid to give the fesoterodine of log D7.4 of 5.7 [156] with the consequent substantial improvement of bioavailability. Fesoterodine is also metabolized by CYP3A4 to N-desisopropylfesoterodine [158], which is presumably inactive in analogy with desisopropyltolterodine. The pKa and log p values of tolterodine and fesoterodine together with the log p value of 5-hydroxymethyltolterodine are given in Figure 34. No corresponding pKa and log p values have been found for N-desisopropyltolterodine or N-desisopropylfesoterodine; however, they can be estimated to be respectively higher and lower than those of tolterodine. Molecules 2021, 26, x FOR PEER REVIEW 23 of 41

9. Muscarinic Receptor Blockers 9.1. Tolterodine/Fesoterodine Tolterodine (Figure 34) is an antimuscarinic drug used in the treatment of overactive bladder (OAB) and urinary urge incontinence. It contains a diisopropylaminopropyl moi- ety. As shown in Figure 34, tolterodine is metabolized through monodeisopropylation to give an inactive metabolite and through benzylic-methyl group oxidation to give 5-hy- droxymethyl tolterodine (5-HMT), which is equiactive with the parent drug [154–157]. Despite being equiactive to its parent drug, 5-HMT did not qualify to the status of metab- olite drug because of its high hydrophilicity (log p value of 0.73) and, accordingly, poor bioavailability [155]. However, the problem has been resolved by esterifying the aromatic hydroxy (phenolic) group with isobutanoic acid to give the prodrug fesoterodine of log D7.4 of 5.7 [156] with the consequent substantial improvement of bioavailability. Fesotero- dine is also metabolized by CYP3A4 to N-desisopropylfesoterodine [158], which is pre- sumably inactive in analogy with desisopropyltolterodine. The pKa and log p values of tolterodine and fesoterodine together with the log p value of 5-hydroxymethyltolterodine are given in Figure 34. No corresponding pKa and log p Molecules 2021, 26, 1917 values have been found for N-desisopropyltolterodine or N-desisopropylfesoterodine;23 of 40 however, they can be estimated to be respectively higher and lower than those of toltero- dine.

OH pKa 9.87 log P 1.81

N CY OH P2 D6 (log P 0.73) Tolterodine Diisopropyl- N CYP3A4 IB aminopropyl A E /H OH s + O OH te 5-Hydroxymethyl- ra se tolferodine (5-HMT) O

N O H O N N-Desisopropyltolterodine CYP3A4 (Inactive) OH Fesoterodine N H pKa 10.47 OH log P 5.7 N-Desisopropylfesoterodine (Presumably inactive)

5-HMT is equipotent with tolterodine. IBA: Isobutanoic acid FigureFigure 34.34. Metabolic pathways pathways of of tolterodine tolterodine and and fesoterodine. fesoterodine.

9.2.9.2. OxybutyninOxybutynin OxybutyninOxybutynin (Figure (Figure 35) 35 is) a is chiral a chiral antimuscar antimuscarinicinic drug used drug in the used treatment in the of treatment over- of overactiveactive bladder. bladder. The R The-enantiomerR-enantiomer of oxybutynin of oxybutynin accounts accountsfor all the forantimuscarinic all the antimuscarinic activ- activityity while while the theS-enantiomerS-enantiomer is inactive is inactive [159]. [159 The]. dr Theug drugcontains contains a diethylaminobutynyl a diethylaminobutynyl moietymoiety and is is metabolized metabolized through through the thepathways pathways depicted depicted in Figure in Figure35 [160–164]. 35[ 160 N–-de-164]. N- sethyloxybutynin has similar activity to oxybutynin as antimuscarinic [159]. The pKa and Molecules 2021, 26, x FOR PEER REVIEWdesethyloxybutynin has similar activity to oxybutynin as antimuscarinic [159]. The24 pKa of 41 log p values of oxybutynin and N-desethyloxybutynin are given in Figure 35. and log p values of oxybutynin and N-desethyloxybutynin are given in Figure 35.

Diethyaminobutynyl

HOH C C N O C C N O O O H HO 1 HO * 1 2 CYP3A4 2

E E s st te er r h as N-Desethyloxybutynin Oxybutynin y e O d OH ro (Active) pKa 8.77 ly HO 1 s is pKa 9.14 log P 4.3 2 log P 3.7

2-Cyclohexyl-2-phenyl * Chiral center glycolic acid (Inactuve)

Figure 35. Metabolic pathways of oxybutynin.

10. “If” Channel Blockers 10.1. Ivabradine IvabradineIvabradine (Figure(Figure 36 36)) is is used used for for the the symptomatic symptomatic management management of stable of stable -related heart-re- chestlated painchestand pain heart and failureheart failure not fully not managed fully managed by beta-blockers. by beta-blockers. Ivabradine Ivabradine lowers lowers heart rateheart by rate selectively by selectively inhibiting inhibi Ifting channels If channels (“funny (“funny channels”) channe inls”) the heartin the in heart a concentration- in a concen- dependenttration-dependent manner manner without without affecting affecting any other an cardiacy other ioniccardiac channels ionic channels (including (including calcium orcalcium potassium) or potassium) [165]. The [165]. drug The contains drug contains a tertiary a methylamino tertiary methylamino moiety and moiety is metabolized and is me- tabolized predominantly in the liver and intestines by the cytochrome P450 (CYP) 3A4 enzyme to active N-desmethylivabradine (S-18982), which circulates at concentrations of approximately 40% [166]. The pKa and log p values of ivabradine are given in Figure 36. No corresponding data have been found for N-desmethylivabradine; however, they can be predicted as, respectively, higher and lower than those of ivabradine.

O O O O N CYP3A4 N O O O O

N HN O Tertiary O methylamino N-Desmethlivabradine Ivabradine (Active) pHa 9.37 log P 2.72 Figure 36. Metabolism of ivabradine.

11. Drugs That Act as Enzyme Inhibitors 11.1. Sildenafil (Figure 37) is a member of a class of called phosphodiesterase (PDE) inhibitors. It is used to treat erectile dysfunction in men as well as pulmonary arte- rial hypertension [167]. It contains a heterocyclic tertiary methylamino moiety, which rep- resents the site of metabolism upon N-demethylation to give N-desmethylsildenafil (Fig- ure 37) [168–171]. The metabolite possesses a PDE5 selectivity that is similar to the parent sildenafil molecule and in vitro for PDE approximately 50% that of the parent drug; it accounts for 20% pharmacologic activity of sildenafil [171]. The pKa and log p values of sildenafil and N-desmethylsildenafil are given in Figure 37.

Molecules 2021, 26, x FOR PEER REVIEW 24 of 41

Diethyaminobutynyl

HOH C C N O C C N O O O H HO 1 HO * 1 2 CYP3A4 2

E E s st te er r h as N-Desethyloxybutynin Oxybutynin y e O d OH ro (Active) pKa 8.77 ly HO 1 s is pKa 9.14 log P 4.3 2 log P 3.7

2-Cyclohexyl-2-phenyl * Chiral center glycolic acid (Inactuve) Figure 35. Metabolic pathways of oxybutynin.

10. “If” Channel Blockers 10.1. Ivabradine Ivabradine (Figure 36) is used for the symptomatic management of stable heart-re- Molecules 2021, 26, 1917 lated chest pain and not fully managed by beta-blockers. Ivabradine lowers24 of 40 by selectively inhibiting If channels (“funny channels”) in the heart in a concen- tration-dependent manner without affecting any other cardiac ionic channels (including calcium or potassium) [165]. The drug contains a tertiary methylamino moiety and is me- predominantlytabolized predominantly in the liver inand the intestinesliver and inte by thestines cytochrome by the cytochrome P450 (CYP) P450 3A4 (CYP) enzyme 3A4 to activeenzymeN -desmethylivabradineto active N-desmethylivabradine (S-18982), (S-18982), which circulates which circulates at concentrations at concentrations of approxi- of matelyapproximately 40% [166 40%]. The[166]. pKa The and pKa log andp logvalues p values of ivabradine of ivabradine are are given given in in Figure Figure 36 36.. No correspondingNo corresponding data data have have been been found found for forN-desmethylivabradine; N-desmethylivabradine; however, however, they they cancan be predictedbe predicted as, respectively,as, respectively, higher higher and and lower lower than than those those of of ivabradine. ivabradine.

O O O O N CYP3A4 N O O O O

N HN O Tertiary O methylamino N-Desmethlivabradine Ivabradine (Active) pHa 9.37 log P 2.72 FigureFigure 36.36. MetabolismMetabolism of ivabradine.

11.11. DrugsDrugs ThatThat Act as Enzyme Inhibitors Inhibitors 11.1.11.1. SildenafilSildenafil SildenafilSildenafil (Figure 37)37) is a a member member of of a a cl classass of of medications medications call calleded phosphodiesterase phosphodiesterase (PDE)(PDE) inhibitors.inhibitors. It It is isused used to treat to treat erectile erectile dysfunction dysfunction in men in as men well as as well pulmonary as pulmonary arte- arterialrial hypertension hypertension [167]. [167 It contains]. It contains a hetero a heterocycliccyclic tertiary tertiary methylamino methylamino moiety, moiety, which rep- which representsresents the thesite siteof metabolism of metabolism upon upon N-demethylationN-demethylation to give to N give-desmethylsildenafilN-desmethylsildenafil (Fig- (Figureure 37) [168–171].37)[168–171 The]. metabolite The metabolite possesses possesses a PDE5 a selectivity PDE5 selectivity that is similar that is to similar the parent to the parentsildenafil sildenafil molecule molecule and in vitro and inpotency vitro potency for PDE forapproximately PDE approximately 50% that 50%of the that parent of the Molecules 2021, 26, x FOR PEER REVIEWparentdrug; it drug; accounts it accounts for 20% for pharmacologic 20% pharmacologic activity activityof sildenafil of sildenafil [171]. The [171 pKa]. The and pKa log25 andp of 41

logvaluesp values of sildenafil of sildenafil and N and-desmethylsildenafilN-desmethylsildenafil are given are in given Figure in Figure37. 37.

Heterocyclic teriary O methylamino HN N O O N S C N N YP O 3A N 4 N O HN O O N S N N Sildenafil HN O pKa 5..99 log P 1.87

N-Desmethylsildenafil

pKa 6.90 log P 0.93

FigureFigure 37. 37.Metabolism Metabolism of of sildenafil. sildenafil.

12.12. Drugs Drugs That That Act Act on on Microorganisms Microorganisms 12.1.12.1. Chloroquine/Hydroxychloroquine Chloroquine/Hydroxychloroquine ChloroquineChloroquine (CQ) (CQ) and and hydroxychloroquine hydroxychloroquine HCQ) HCQ) (Figures (Figures 38 and 38 and39, respectively) 39, respectively) are aminoquinolonesare aminoquinolones that inhibit that inhibit polymerase; polymerase; they are they used are in used thetreatment in the treatment and prophylaxis and prophy- of malaria.laxis of Inmalaria. order toInstop order malaria, to stop they malaria, cause they the accumulationcause the accumulation of heme, which of heme, is toxic which and is deadlytoxic and to the deadly parasite. to the The parasite. heme is The accumulated heme is accumulated due to the inhibition due to the of hemeinhibition polymerase of heme thatpolymerase takes place that [172 takes]. However, place [172]. the However, use of CQ the and use HCQ of CQ in the and treatment HCQ in the and treatment prophylaxis and ofprophylaxis malaria has of declined malaria has because declined of development because of development of resistance of [ 173resistance]. Currently, [173].Currently, both CQ andboth HCQ CQ haveand HCQ made have a notable made comeback a notable incomeba chemotherapyck in in the treatment in the of treatment Covid-19. of DrugsCovid-19. repurposing Drugs repurposing (adaptation (adaptation for use in a for different use in purpose)a different to purpose) fall into theto fall treatment into the regimetreatment of COVID-19, regime of COVID-19, are currently are being currently tested. being They tested. fall into They one fall of theinto two onefollowing of the two following categories: (i) drugs that target the replication cycle of the virus, and (ii) drugs that aim at controlling the disease’s symptoms. In view of the treatment for COVID-19, it is suggested that the CQ and HCQ work by inhibiting the entry of the virus into the host cells. The mechanism involves blocking the host receptors’ glycosylation, along with breaking down the formation of the virus proteins by inhibiting endosomal acidification by virtue of the drugs being basic in character, since each drug contains two basic nitro- gens (i.e., each drug is a diacidic base) [174–178]. Even though there is a clear lack of adequate evidence of benefit of the drugs,many African and other countries have endorsed hydroxychloroquine repurposed (off-label) use for the treatment of COVID-19 contrary to the WHO recommendations [179]. On the other hand, the US Food and Drug Administration have also issued an Emergency Use Authorization for the use of chloroquine and hydroxychloroquine for the treatment of Covid-19 in adult populations [180]. Chloroquine contains a diethylaminopentyl moiety and is metabolized by sequential N-deethylation to N-desethylchloroquine and N,N-didesethylchloroquine as depicted in Figure 38 [181–187]. The two metabolites are respectively formed in 40% and 10% yields with respect to chloroquine. Both chloroquine and desethylchloroquine concentrations decline slowly, with elimination half-lives of 20 to 60 days. Both parent drug and metab- olite can be detected in urine months after a single dose [164]. Interestingly, one literature report [177] mentions HCQ as a metabolite of CQ; however, this statement has not been substantiated by other reports on CQ metabolism. On the other hand, hydroxychloro- quine contains ethyl/hydroxyethylene groups and is metabolized by sequential removal of the two groups as shown in Figure 39 [174,188,189]. The pKa and log p values for chloroquine and hydroxychloroquine are given in Fig- ures 38 and 39, respectively. Despite lack of pKa and log p values for desethylhydroxy chloroquine in the literature, predictions can be made. Secondary amino groups are in- variably more basic and more polar with higher pKa and lower log p values than tertiary

Molecules 2021, 26, 1917 25 of 40

categories: (i) drugs that target the replication cycle of the virus, and (ii) drugs that aim at controlling the disease’s symptoms. In view of the treatment for COVID-19, it is suggested Molecules 2021, 26, x FOR PEER REVIEWthat the CQ and HCQ work by inhibiting the entry of the virus into the host cells.26 The of 41

Molecules 2021, 26, x FOR PEER REVIEWmechanism involves blocking the host receptors’ glycosylation, along with breaking down26 of 41

the formation of the virus proteins by inhibiting endosomal acidification by virtue of the drugs being basic in character, since each drug contains two basic nitrogens (i.e., each drug amino groups. Extrapolation can be extended to hydroxychloroquine and desethylhy- is a diacidic base) [174–178]. aminodroxychloroquine. groups. Extrapolation can be extended to hydroxychloroquine and desethylhy- droxychloroquine. Diethylaminopropyl Diethylaminopropyl pKa 10.62 H pKa 10.62 N pKa 10.32 N HN HN H N pKa 10.32 N HN CYP3A4 HN CYP3A4 Cl N Chloroquine CYP2C8 Cl N Cl N Chloroquine CYP2C8A4 Cl N P3 N-desethylchloroquine CY 4 8 pKa 8.4 3A 2C P YP N-desethylchloroquinelog P 3.19 CY C C8 logpKa P 8.43.93 P2 CNHY 2 log P 3.19 log P 3.93 HN (Major avtive metabolite) NH2 HN (Major avtive metabolite)

Cl N Cl N,N-didesethylchloroquineN N,N-didesethylchloroquine (Minor active metabolite) (Minor active metabolite) FigureFigure 38. 38.Major Major metabolic metabolic pathways pathways of of chloroquine. chloroquine. Figure 38. Major metabolic pathways of chloroquine.

CH2OH

N pKaCH 9.672OH Hydroxchloroquine HN * N pKa 9.67 Hydroxchloroquine HN * Ethyl-hydroxyethylaminopropyl Ethyl-hydroxyethylaminopropyl Cl N R CYP3A4 Cl N R * Chiral carbon CYP3A4 pKa 8.1 * Chiral carbon log PpKa 2.89 8.1 H H log P 2.89 NH NH R R + OH N N R R NH R + OH 2 Deshydroxyethyl- Desethylhydroxy- R NH2 chloroquine Didesethyl- Deshydroxyethyl-chloroquine (1) Desethylhydroxy- choroquine chloroquine Didesethyl- chloroquine (1) choroquine Figure 39. Metabolism of hydroxychloroquine. FigureFigure 39. 39.Metabolism Metabolism of of hydroxychloroquine. hydroxychloroquine. 13. Anticancer Drugs 13.13.1. AnticancerEven Imatinib though Drugs there is a clear lack of adequate evidence of benefit of the drugs, many African and other countries have endorsed hydroxychloroquine repurposed (off-label) 13.1. Imatinib (Figure 40) is first-line therapy for the treatment for all phases of chronic use for the treatment of COVID-19 contrary to the WHO recommendations [179]. On the Imatinib (Figure 40) is first-line therapy for the treatment for all phases of chronic othermyelogenous hand, the US Food and metastatic Drug Administration and unresectable have alsomalignant issued gastrointestinal an Emergency Use stro- myelogenous leukemia and metastatic and unresectable malignant gastrointestinal stro- Authorizationmal tumors [190]. for the Imatinib use of contains chloroquine a heterocyclic and hydroxychloroquine tertiary methylamino for the moiety, treatment which of is mal tumors [190]. Imatinib contains a heterocyclic tertiary methylamino moiety, which is Covid-19metabolized in adult by CYP3A4 populations oxidative [180]. N-demethylation to give N-desmethylimatinib, which metabolized by CYP3A4 oxidative N-demethylation to give N-desmethylimatinib, which is ofChloroquine similar potency contains to the a diethylaminopentylparent drug [191–193]. moiety According and is metabolizedto Foye (2013) by [192], sequential the N- Nismethyl-deethylation of similar substituent potency to N-desethylchloroquine on to the the parent drug ring [1 and91–193]. in imatinibN,N-didesethylchloroquine According has the torole Foye of increasing (2013) as depicted[192], the the water inN- Figuremethylsolubility 38 substituent[ 181 and–187 bioavailability]. on The the two piperazine metabolites profile ofring the are in drug; respectivelyimatinib i.e., it has playsformed the anrole auxophoric in of 40% increasing and role. 10% the The yields water pKa withsolubilityand respectlog p andvalues to bioavailability chloroquine. of imatinib Both andprofile N chloroquine-desmethylimatinib of the drug; and i.e., desethylchloroquine it plays are given an auxophoric in Figure concentrations 40. role. The pKa declineand log slowly, p values with of eliminationimatinib and half-lives N-desmethylimatinib of 20 to 60 days. are Both given parent in Figure drug and 40. metabolite can be detected in urine months after a single dose [164]. Interestingly, one literature

Molecules 2021, 26, 1917 26 of 40

report [177] mentions HCQ as a metabolite of CQ; however, this statement has not been substantiated by other reports on CQ metabolism. On the other hand, hydroxychloroquine contains ethyl/hydroxyethylene groups and is metabolized by sequential removal of the two groups as shown in Figure 39[174,188,189]. The pKa and log p values for chloroquine and hydroxychloroquine are given in Figures 38 and 39, respectively. Despite lack of pKa and log p values for desethylhydroxy chloroquine in the literature, predictions can be made. Secondary amino groups are in- variably more basic and more polar with higher pKa and lower log p values than tertiary amino groups. Extrapolation can be extended to hydroxychloroquine and desethylhydrox- ychloroquine.

13. Anticancer Drugs 13.1. Imatinib Imatinib (Figure 40) is first-line therapy for the treatment for all phases of chronic myelogenous leukemia and metastatic and unresectable malignant gastrointestinal stromal tumors [190]. Imatinib contains a heterocyclic tertiary methylamino moiety, which is metabolized by CYP3A4 oxidative N-demethylation to give N-desmethylimatinib, which is of similar potency to the parent drug [191–193]. According to Foye (2013) [192], the N-methyl substituent on the piperazine ring in imatinib has the role of increasing the water Molecules 2021, 26, x FOR PEER REVIEW 27 of 41 solubility and bioavailability profile of the drug; i.e., it plays an auxophoric role. The pKa and log p values of imatinib and N-desmethylimatinib are given in Figure 40.

Heterocyclic tertiary N methylamino

N

H HH CY N NN N P3 A4 N O N

Imatinib HH NN N pKa 8.27 N O log P 4.38 pKa 9.23 N-desmethylimatinib log P 3.99 (Norimatinib)

FigureFigure 40. 40.Metabolism Metabolism of imatinib. of imatinib.

13.2. Dacarbazine 13.2. Dacarbazine Dacarbazine (Figure 41) is an anticancer alkylating prodrug used in the treatment of Hodgkin’sDacarbazine , (Figure metastatic 41) is melanomaan anticancer and soft alkylating tissue sarcoma prodrug [194, 195used]. Gen-in the treatment of erationHodgkin’s of the lymphoma, alkylating species, metastatic methyl melanoma diazonium, fromand dacarbazinesoft tissue sarcoma occurs through [194,195]. a Generation combinationof the alkylating of metabolic species, processes methyl including diazonium,N-demethylation from dacarbazine as a first step occurs followed through by a combina- tautomerization and spontaneous cleavage as shown in Figure 38[195]. tion of metabolic processes including N-demethylation as a first step followed by tautom- erization and spontaneous cleavage as shown in Figure 38 [195].

O O NH 1 NH2 2 1A N - N P HCH CY 2 O 1A YP N N N N O C E1 P2 H CH2OH H H CY N N NH2 N N N Hydroxy- N-Desmethyl- CH dacarbazine CH3 dacarbazine tmzn 3 N N CH O H 3 O N N NH2 Dacarbazine NH2 N CH3 N SC N N CH3 + N NH N NH2 Dimethylamino H H Methyl H N diazonium N CH DNA-alkylating agent SC: spontaneous cleavage 3 tmzn: tautomerization Figure 41. Metabolic activation of dacarbazine.

13.3. Tamoxifen Tamoxifen (Figure 42) is an , which acts as anti-breast by compet- itively blocking the receptor [196]. It contains a dimethylaminoethoxy moiety and is metabolized through the pathways depicted in Figure 42 [197–204]. While the bind- ing affinity of 4-hydroxytamoxifen to the estrogenic receptor is 30–100 fold stronger than that of tamoxifen, the N-desmethyl metabolite binding affinity is less than that of tamoxi- fen; the N,N-didesmethyl metabolite has even less binding affinity than the N-desmethyl metabolite [199]. Further, containing a tertiary dimethylamino moiety, tamoxifen is me- tabolized by N-oxidation to tamoxifen-N-oxide, which is devoid of estrogen-receptor blocking activity. The pKa and log p values of tamoxifen, N-desmethyltamoxifen, 4-hy- droxytamoxifen (afimoxifene) and 4-hydroxy-N-desmethyltamoxifen () are given in Figure 42.

Molecules 2021, 26, x FOR PEER REVIEW 27 of 41

Heterocyclic tertiary N methylamino

N

H HH CY N NN N P3 A4 N O N

Imatinib HH NN N pKa 8.27 N O log P 4.38 pKa 9.23 N-desmethylimatinib log P 3.99 (Norimatinib) Figure 40. Metabolism of imatinib.

13.2. Dacarbazine Dacarbazine (Figure 41) is an anticancer alkylating prodrug used in the treatment of Hodgkin’s lymphoma, metastatic melanoma and soft tissue sarcoma [194,195]. Generation Molecules 2021, 26, 1917 of the alkylating species, methyl diazonium, from dacarbazine occurs through a combina-27 of 40 tion of metabolic processes including N-demethylation as a first step followed by tautom- erization and spontaneous cleavage as shown in Figure 38 [195].

O O NH 1 NH2 2 1A N - N P HCH CY 2 O 1A YP N N N N O C E1 P2 H CH2OH H H CY N N NH2 N N N Hydroxy- N-Desmethyl- CH dacarbazine CH3 dacarbazine tmzn 3 N N CH O H 3 O N N NH2 Dacarbazine NH2 N CH3 N SC N N CH3 + N NH N NH2 Dimethylamino H H Methyl H N diazonium N CH DNA-alkylating agent SC: spontaneous cleavage 3 tmzn: tautomerization

FigureFigure 41.41.Metabolic Metabolic activationactivation ofof dacarbazine.dacarbazine.

13.3.13.3. TamoxifenTamoxifen TamoxifenTamoxifen (Figure (Figure 42 42)) is is an an antiestrogen, antiestrogen, which which acts acts as as anti-breast anti- cancer by by competi- compet- tivelyitively blocking blocking the the estrogen estrogen receptor receptor [196 [196]]. It contains. It contains a dimethylaminoethoxy a dimethylaminoethoxy moiety moiety and isand metabolized is metabolized through through the pathways the pathways depicted depicted in Figure in Figure 42[ 19742 [197–204].–204]. While While the the binding bind- affinitying affinity of 4-hydroxytamoxifen of 4-hydroxytamoxifen to the to estrogenic the estrog receptorenic receptor is 30–100 is 30–100 fold strongerfold stronger than thatthan ofthat tamoxifen, of tamoxifen, the N -desmethylthe N-desmethyl metabolite metabolite binding binding affinity affinity is less thanis less that than of tamoxifen;that of tamoxi- the Nfen;,N-didesmethyl the N,N-didesmethyl metabolite metabolite has even has less even binding less affinitybinding than affinity the Nthan-desmethyl the N-desmethyl metabo- litemetabolite [199]. Further, [199]. Further, containing containing a tertiary a dimethylaminotertiary dimethylamino moiety, tamoxifen moiety, tamoxifen is metabolized is me- bytabolizedN-oxidation by N to-oxidation tamoxifen- toN -oxide,tamoxifen- whichN-oxide, is devoid which of estrogen-receptor is devoid of estrogen-receptor blocking activ- Molecules 2021, 26, x FOR PEER REVIEWity. The pKa and log p values of tamoxifen, N-desmethyltamoxifen, 4-hydroxytamoxifen28 of 41 blocking activity. The pKa and log p values of tamoxifen, N-desmethyltamoxifen, 4-hy- (afimoxifene)droxytamoxifen and (afimoxifene) 4-hydroxy-N-desmethyltamoxifen and 4-hydroxy-N-desmethyltamoxifen (endoxifen) are given (endoxifen) in Figure 42 .are given in Figure 42.

O H3C O N CYP3A4 N CH H 3 (N-demethylation) CH3 Tamoxifen N-Desmethyltamoxifen (Active) pKa 8.76 pKa 9.51 log P 5.97

log P 6.35 C Y O P 2 N D CYP2D6 6 O CH3 pKa 8.66 H C O Tamoxifen-N-oxide pKa 9.74 3 N (Inactive) H3C O CH N CH 3 3 H CH CYP3A4 3 4-Hydroxytamoxifen Endoxifen (afimoxifene,, (Active metabolite) active metabolite) OH pKa 9.45 log P 4.92 OH log P 4.48 pKa 9.12 Figure 42. Metabolic pathways of tamoxifen. Figure 42. Metabolic pathways of tamoxifen.

13.4.13.4. TormifeneTormifene TormifeneTormifene (Figure 43)43) is is a a fi first-generationrst-generation nonsteroidal nonsteroidal selective selective estrogen estrogen receptor receptor modulatormodulator [205].It [205]. Ithas has beneficial beneficial effects effects on the on bone, the bone, and cardiovascular and cardiovascular system; system;besides, be- sides,it increases it increases HDL levels HDL [205]. levels Its [205 structure]. Its structureis very similar is very to similarthat of tamoxifen; to that of the tamoxifen; two thedrugs two differ drugs only differ in a chloro only in group a chloro in the group side ethyl in the chain side of ethyl tormifene. chain Similar of tormifene. to tamox- Sim- ilarifen, to tormifene tamoxifen, contains tormifene a dimethylaminoeth contains a dimethylaminoethoxyoxy chain where metabolic chain changes where occur metabolic as changesdepicted occurin Figure as depicted40. Analogous in Figure to tamoxifen, 40. Analogous tormifene to is tamoxifen,metabolized tormifene to N-desmethyl- is metab- tormifene, 4-hydroxytormifene-N-desmethyltormifene tormifene-N-oxide [206–208] and olized to N-desmethyltormifene, 4-hydroxytormifene-N-desmethyltormifene tormifene- ospermifene [209] as depicted in Figure 43. Although the activities of the first two metab- N-oxide [206–208] and ospermifene [209] as depicted in Figure 43. Although the activ- olites relative to the tormifene are not reported in the literature, they can be inferred from the activities of metabolites of the closely related drug tamoxifen: N-desmethyltormifene is expected to have little activity while 4-hydroxy-N-desmethyltormifene has significant activity. Ospermifene is a selective estrogen- [205]. The pKa and log p values of tormifene are given in Figure 43. The corresponding values for the N-desmethyl metabolite of tormifene were not available, but can be inferred as higher as and lower than those of tormifene, respectively.

Dimethylaminoethoxy H N N OH O O O

CYP3A4

pKa 8.76 Cl Cl Cl log P 6.27 Ospermifene N-Desmethyltoremifene Selective estrogen- F C CYP2D6 M Y receptor modulator P O 2 D O 6 H N N O O N O

5 OH 6 4 OH 4 1 3 2 Cl Cl Cl 4-Hydroxytormifene Tormifene-N-oxide 4-Hydroxy-N-desmehyltormifene (Inactve) Figure 43. Metabolic pathways of tormifene.

Molecules 2021, 26, x FOR PEER REVIEW 28 of 41

O H3C O N CYP3A4 N CH H 3 (N-demethylation) CH3 Tamoxifen N-Desmethyltamoxifen (Active) pKa 8.76 pKa 9.51 log P 5.97

log P 6.35 C Y O P 2 N D CYP2D6 6 O CH3 pKa 8.66 H C O Tamoxifen-N-oxide pKa 9.74 3 N (Inactive) H3C O CH N CH 3 3 H CH CYP3A4 3 4-Hydroxytamoxifen Endoxifen (afimoxifene,, (Active metabolite) active metabolite) OH pKa 9.45 log P 4.92 OH log P 4.48 pKa 9.12 Figure 42. Metabolic pathways of tamoxifen.

13.4. Tormifene Tormifene (Figure 43) is a first-generation nonsteroidal selective estrogen receptor modulator [205].It has beneficial effects on the bone, and cardiovascular system; besides, it increases HDL levels [205]. Its structure is very similar to that of tamoxifen; the two drugs differ only in a chloro group in the side ethyl chain of tormifene. Similar to tamox- Molecules 2021, 26, 1917 28 of 40 ifen, tormifene contains a dimethylaminoethoxy chain where metabolic changes occur as depicted in Figure 40. Analogous to tamoxifen, tormifene is metabolized to N-desmethyl- tormifene, 4-hydroxytormifene-N-desmethyltormifene tormifene-N-oxide [206–208] and itiesospermifene of the first [209] two as metabolitesdepicted in Figure relative 43. toAl thethough tormifene the activities are not of the reported first two in metab- the litera- ture,olites they relative can to be the inferred tormifene from are the not activitiesreported in of the metabolites literature, they of the can closely be inferred related from drug tamoxifen:the activitiesN -desmethyltormifeneof metabolites of the closely is expected related todrug have tamoxifen: little activity N-desmethyltormifene while 4-hydroxy- N- desmethyltormifeneis expected to have little has significantactivity while activity. 4-hydroxy- OspermifeneN-desmethyltormifene is a selective estrogen-receptorhas significant activity. Ospermifene is a selective estrogen-receptor modulator [205]. The pKa and log p modulator [205]. The pKa and log p values of tormifene are given in Figure 43. The values of tormifene are given in Figure 43. The corresponding values for the N-desmethyl corresponding values for the N-desmethyl metabolite of tormifene were not available, but metabolite of tormifene were not available, but can be inferred as higher as and lower than can be inferred as higher as and lower than those of tormifene, respectively. those of tormifene, respectively.

Dimethylaminoethoxy H N N OH O O O

CYP3A4

pKa 8.76 Cl Cl Cl log P 6.27 Ospermifene Toremifene N-Desmethyltoremifene Selective estrogen- F C CYP2D6 M Y receptor modulator P O 2 D O 6 H N N O O N O

5 OH 6 4 OH 4 1 3 2 Cl Cl Cl 4-Hydroxytormifene Tormifene-N-oxide 4-Hydroxy-N-desmehyltormifene (Inactve) FigureFigure 43. 43.Metabolic Metabolic pathways of of tormifene. tormifene.

14. Metabolic N-Dealkylation and N-Oxidation 14.1. Metabolic N-Dealkylation The following observations can be made from the cited drug cases: (1) In drugs containing aliphatic open-chain tertiary N,N-dialkylamino moieties, the alkyl groups are methyl, ethyl or isopropyl. (2) In drugs containing heterocyclic tertiary N-alkylamino moieties, the ring is either piperidine or piperazine and the alkyl group is invariably methyl. (3) N-dealkylation of aliphatic tertiary N,N-dialkylamino moieties is sequential for some drugs giving rise to secondary N-alkylamino moieties and primary amino groups. (4) As far as pKa values are concerned, N-dealkylation of N-alkylamino moieties invari- ably results in situations where pKa (3◦ amine) < pKa (2◦ amine) > pKa (1◦ amine) for all the reviewed drug cases. (5) For log p values, the corresponding order is log p (3◦ amine) > log p (2◦ amine) > log p (1◦ amine). (6) The N-desalkyl metabolites of tertiary and secondary-alkylamino-moiety-containing parent drugs vary in pharmacologic activities being more active, equiactive (some- times with alteration in the mechanism of action), less active or inactive. The pKa and log p values of the parent drugs and their N-desalkyl metabolites have been obtained from DrugBank [210]. Where the corresponding pKa and log p data are not available for the N-desalkyl metabolites, they can generally be inferred as higher and lower, respectively, than those of the parent drugs. The order of the pKa values of the three amine classes is pKa (N,N-dialkylamino) < pKa (N-monoalkylamino) > (primary amino), and is explicable by electronic and steric effects [211,212]. On the other hand, the order of the corresponding log p values is log p (N,N-dialkylamino) > log p (N-monoalkylamino) > log p (primary amino), which is due to Molecules 2021, 26, 1917 29 of 40

reduced polarity and hence reduced water solubility and enhanced lipid solubility of the amino-group-containing compound from left to right. The electronic and steric effects on N-alkylamino moieties can be explained as thus: alkyl groups (such as methyl, ethyl and isopropyl) are electron-donating (or electron- releasing) groups. Hence, in N-alkylamino moieties, the alkyl groups will tend to increase the electron density on the nitrogen, rendering it more basic (i.e., with higher pKa value). The increase of basicity will lead to increase in the concentration of the protonated (ionized) form of the compound relative to the unionized form as can be calculated by the Henderson- Hasselbalch equation [213]. On the other hand, however, when an alkyl group replaces the hydrogen atom of the secondary N-alkylamino moiety it will exert a steric effect. This steric effect will hinder the approach of a proton (H+) to access the lone pair of electrons on the nitrogen of the resulting tertiary N,N-dialkylamino moiety. The result of the steric effect is hence decrease of the basicity of N,N-dialkylamino moieties relative to N-monoalkylamino moieties. In summary, the electronic effect is manifest in secondary and tertiary alkylamino moieties relative to primary amino moieties, while the steric effect explains the decrease of the basicity of tertiary N,N-alkylamino moieties relative to secondary N-alkylamino moieties. Therefore, the implication of the electronic and steric effects is that the secondary alkylamino moieties in N-monoalkylamino metabolites will be more protonated (ionized) than tertiary N,N-alkylamino moieties in the parent drugs. Accordingly, if the ionic (salt bridge) binding of the alkylamino moiety to the receptor is an essential pharmacophoric character, then with equimolar amounts of the parent drug and its N-desalkyl metabolite, the latter should have more affinity to the receptor and possibly higher efficacy than its parent drug. As well, hydrogen-bonding interactions are more manifest in secondary N- alkylamino moieties, which act as both hydrogen-bond acceptors and donors, as compared to tertiary N,N-dialkylamino moieties, which only act as relatively weak hydrogen-bond acceptors. Accordingly, assuming that ionic and hydrogen-bond bindings play a crucial role in determining the affinity of alkylamino-moiety-containing drugs, one would expect the secondary alkylamino metabolites to be more active than the tertiary-alkylamino- moiety-containing parent drugs. However, in all the cited drug cases in this review this has not been observed to be the case as factors other than affinity to drug receptors govern the pharmacologic activity of metabolites as will be discussed in due course. Shein and Smith (1978) [214] stated that in TCAs, amine substitution by alkyl groups does not alter ionization of the nitrogen in both imipramine and desmipramine “as both compounds have pKa values of 9.5”. To quote the authors [214], “Despite the high percentage ionization of this group (the monoalkylamino in desmipramine or dialkylamino in imipramine) at the pH of the Tyrode solution (presumably pH 7.4), attachment of the terminal part of the side chain is largely nonpolar in type”. We tend to differ with this statement [214], which may not be, in totality, true as the steric effect in the tertiary dimethylamino moiety in imipramine entails lower basicity (lower pKa) than the secondary alkylamino moiety in desmipramine as is evident from the pKa values of the two drugs, 9.2 and 10.02, respectively. We argue that the amino groups play a significant role in the attachment of the side chain to the receptor through ionic and hydrogen-bonding interactions. This argument is substantiated by literature reports [215–217]. Further, the decrease of log p of secondary-alkylamino-moiety-containing metabolites relative to tertiary- alkylamino-moiety-containing parent drugs is due to the ability of the secondary alkylamino moieties to act as both hydrogen-bond donors and acceptors while the tertiary alkylamino moieties act as only hydrogen-bond acceptors. Accordingly, the sec- ondary alkylamino moieties are able to establish more hydrogen bonds with water than the tertiary alkylamino moieties. The inference is that the aqueous solubility of the secondary alkylamino metabolites will increase with the subsequent decrease of log p relative to the tertiary alkylamino parent drugs. The literature log p values of the dialkylamino parent drugs and the alkylamino metabolites given in the figures are invariably in line with the above prediction. Molecules 2021, 26, 1917 30 of 40

Both the effects of pKa and log p modifications by metabolic N-dealkylation tend to impede penetration of the N-desalkylamino metabolites of lipophilic cell membranes, thus leading to decrease in the effective concentrations of the metabolites at the receptor resulting in attenuation of pharmacologic activity in most of the cited drug cases. The attenuation of the pharmacologic activity of the N-desalkylamino metabolites may occur despite the fact that they may have stronger affinities for the receptor than the dialkylamino- moiety-containing parent drugs as has been argued earlier. Sahu et al. [218] have associated the decrease of log p of the anti-HIV tetrahydroimidazobenzodiazepinones with decrease in pharmacologic activity, however, without explicitly giving the reason.

14.1.1. Focused N-Dealkylation Cases Attenuation or retaining of pharmacologic activity has been observed for most of the N-monodesalkyl metabolites of the drug cases cited in this review and are explicable by the physicochemical differences between the metabolites and parent drugs. However, other cases, which help in elucidating the role of alkylamino moieties in drug molecules acting at various receptors have also been observed and are thus focused.

14.1.1.1. Loss of Pharmacologic Activity Loss of pharmacologic activity of the N-monodesalkyl metabolites with respect to the N,N-dialkylamino parent drugs has been reported for some cases. These drugs include the antidepressant venlafaxine (Section 2.1.3, Figure6)[ 219,220], the analgesic tramadol (Section 5.2, Figure 23)[221] and the antimuscarinic tolterodine (Section 9.1, Figure 31)[222]. Loss of pharmacologic activity is usually associated with loss or modification of a phar- macophoric structural feature in the original drug molecule. We therefore argue that since N-alkyl groups in drug molecules do not form hydrogen or ionic bonds with receptors, abolishment of pharmacologic activity upon their loss by metabolic N-dealkylation is explicable by both alkyl groups in N,N-dialkylamino moieties in venlafaxine, tramadol and tolterodine playing primary pharmacophoric roles. The binding of the two-alkyl groups to the receptors via van der Waals forces is crucial for affinity and accordingly to the efficacy and activity of the parent drugs. The same phenomenon may be extrapolated to secondary alkylamino parent drugs upon their metabolic N-dealkylation to primary amines. Further, the alkyl groups of the N.N-dialkylamino moieties in venlafaxine, tramadol and toltero- dine may play a logistic pharmacophoric role of orienting the protonated nitrogen of the alkylamino moieties for optimum binding to the aspartate amino-acid residues in the corresponding receptors [223,224]. On the other hand, three drugs have been noted for the complete metabolic loss of the pharmacophoric alkylamino moieties with the consequent loss of pharmacologic activity: diphenhydramine to diphenylmethoxyacetic acid (Section 4.1, Figure 22), oxybutynin to 2-cyclohexyl-2-phenylglycolic acid (Section 9.2, Figure 35) and tormifene to ospermifene (Section 13.4, Figure 43). In tormifene, the metabolic loss of the alkylamino moiety has led to alteration of the mechanism of the metabolite, ospermifene, to modulator rather than blocker of the estrogenic receptor as is the case with the parent drug. In addition, diphenhydramine is metabolized to inactive N-acetyl-N-desmethyldiphenhydramine in which the amide group is only capable of hydrogen-bond binding to the receptor but not of ionic binding since it (the amide group) is not ionizable. The latter observation gives supporting evidence to the importance of receptor ionic binding of the N,N-dimethylamino and N-methylamino moieties in the parent drug and metabolite, respectively.

14.1.1.2. Modification of Receptor Inhibition Selectivity Metabolic N-demethylation of tertiary dimethylamino moieties has resulted in the modification of receptor inhibition selectivity as exemplified by the TCAs imipramine to desmipramine and amitriptyline to nortriptyline (Section 2.1.1, Figures3 and4, respec- tively). The parent drugs, imipramine and amitriptyline, are more selective inhibitors of serotonin transport receptor (SET) than norepinephrine transport receptor (NET) while the Molecules 2021, 26, 1917 31 of 40

opposite effect is true for the respective metabolite drugs, desmipramine and nortriptyline. This shift in receptor inhibition selectivity may be explained by two possibilities. Firstly, the two pharmacophoric methyl groups in the parent drugs (imipramine and amitriptyline) bind to the SET receptor via van der Waal’s forces as opposed to the one-methyl-group binding in the N-desmethyl metabolite drugs (desmipramine and nortriptyline). Secondly, the hydrogen bond and ionic bindings are more manifested in the N-desmethyl metabolite drugs to the NET receptor relevant to the parent drugs. According to Goral et al. [223], the methyl groups in the dimethylamino moiety may help in orienting the protonated amino groups in the drug and metabolites for optimum ion-ion binding with the receptor. A quote from Goral et al.’s paper [223] is thus, “ D75 plays a key role in recognition of the basic amino group present in inhibitors and substrates”. Substantiating evidence in this respect is found in the work by Patil et al. [224] and Maria et al. [225]. A quote from Patil et al.’s paper [224] is thus: “The results presented here demonstrate that hydrogen bonding and optimized hydrophobic interactions both stabilize the ligands at the target site, and help alter binding affinity and drug efficacy”. A quote from López-Rodríguez et al.’s pa- per [225] is thus, “ receptor ligands docking: Forty-five structurally diverse 5-hydroxytryptamine6 receptor (5-HT6R) antagonists were selected to develop a 3D model with the Catalyst software. The structural features for antagonism at this receptor are a positive ionizable atom interacting with Asp3.32, a hydrogen bond acceptor group interacting with Ser5.43 and Asn6.55, a hydrophobic site interacting with residues in a hydrophobic pocket between transmembranes 3, 4, and 5, and an aromatic-ring hydrophobic site interacting with Phe6.52”.

14.1.1.3. Activation of Prodrugs An example where metabolic N-demethylation of N,N-dimethylamino moiety has resulted in the active form of the drug is dacarbazine (an anticancer drug), which is trans- formed to the DNA-alkylating entity methyl diazonium. Methyl diazonium results from the successive processes of metabolic N-demethylation, tautomerization and spontaneous cleavage of the prodrug dacarbazine as shown in Figure 41. Thus, dacarbazine is a prodrug that is activated in vivo by metabolic and chemical processes. The first crucial step is the metabolic N-demethylation.

14.1.1.4. Potential Drug Candidates (Metabolite Drugs) Metabolic N-demethylation as well as 4-hydroxylation are essential steps in the for- mation of active forms of the breast cancer drug, tamoxifen (Section 13.3, Figure 42). 4-Hydroxytamoxifen (afimoxifene) [226] and N-desmethyl-4-hydroxytamoxifen (endox- ifen) [200] are presently in the final phases of development as drugs for the treatment of breast cancer. After they have qualified for clinical use, the two candidate drugs will bypass the use of the prodrug tamoxifen and will be of benefit for breast-cancer patients who lack the enzyme CYP2D6, which activates tamoxifen in vivo. Chloroquine and hydroxychloroquine are used as antivirals in some drug treatment protocols of Covid-19. The mechanism of the antiviral action of both drugs has been suggested as being due to the inhibition of endosomal acidification by virtue of the basicity of the two drugs since each of them contains two basic nitrogens, i.e., the two drugs are diacidic bases (Section 12.1, Figures 38 and 39)[175–179]. If this theory of the mechanism of action were to be endorsed, then the N-desethyl metabolites of the two drugs are expected to be more efficacious as antiviral agents than the parent drugs due to their higher basicity. The fact that 40% of a dose of chloroquine is metabolized to N-desethylchloroquine consolidates the possible participation of the N-desethyl metabolite in the antiviral activity based on the basicity theory. Accordingly, thought may have to be given to consider the N- desethyl metabolites of chloroquine and hydroxychloroquine as potential drug candidates and develop them into fully-fledged drugs against Covid-19. Molecules 2021, 26, x FOR PEER REVIEW 32 of 41

14.1.1.3. Activation of Prodrugs An example where metabolic N-demethylation of N,N-dimethylamino moiety has resulted in the active form of the drug is dacarbazine (an anticancer drug), which is trans- formed to the DNA-alkylating entity methyl diazonium. Methyl diazonium results from the successive processes of metabolic N-demethylation, tautomerization and spontaneous cleavage of the prodrug dacarbazine as shown in Figure 41. Thus, dacarbazine is a pro- drug that is activated in vivo by metabolic and chemical processes. The first crucial step is the metabolic N-demethylation.

14.1.1.4. Potential Drug Candidates (Metabolite Drugs) Metabolic N-demethylation as well as 4-hydroxylation are essential steps in the for- mation of active forms of the breast cancer drug, tamoxifen (Section 13.3, Figure 42). 4- Hydroxytamoxifen (afimoxifene) [226] and N-desmethyl-4-hydroxytamoxifen (endoxi- fen) [200] are presently in the final phases of development as drugs for the treatment of breast cancer. After they have qualified for clinical use, the two candidate drugs will by- pass the use of the prodrug tamoxifen and will be of benefit for breast-cancer patients who lack the enzyme CYP2D6, which activates tamoxifen in vivo. Chloroquine and hydroxychloroquine are used as antivirals in some drug treatment protocols of Covid-19. The mechanism of the antiviral action of both drugs has been sug- gested as being due to the inhibition of endosomal acidification by virtue of the basicity of the two drugs since each of them contains two basic nitrogens, i.e., the two drugs are diacidic bases (Section 12.1, Figures 38 and 39) [175–179]. If this theory of the mechanism of action were to be endorsed, then the N-desethyl metabolites of the two drugs are ex- pected to be more efficacious as antiviral agents than the parent drugs due to their higher basicity. The fact that 40% of a dose of chloroquine is metabolized to N-desethylchloro- quine consolidates the possible participation of the N-desethyl metabolite in the antiviral activity based on the basicity theory. Accordingly, thought may have to be given to con- Molecules 2021, 26, 1917 sider the N-desethyl metabolites of chloroquine and hydroxychloroquine as potential32 of 40 drug candidates and develop them into fully-fledged drugs against Covid-19.

14.2. N-Oxidation of Tertiary-Alkylamino-Moiety-Containing Drugs 14.2. N-Oxidation of Tertiary-Alkylamino-Moiety-Containing Drugs The following observations have been made from the cited drug cases metabolized by NThe-oxidation: following observations have been made from the cited drug cases metabolized by N-oxidation: (1) N-oxidation has been observed for only tertiary alkylamino groups (aliphatic open- (1) Nchain-oxidation or heterocyclic), has been observed but not for for second only tertiaryary alkylamino alkylamino or primary groups (aliphaticamino groups. open- (2) chainRegarding or heterocyclic), pharmacologic but not activity, for secondary N-oxides alkylamino of all the reviewed or primary drug amino cases groups. are inac- (2) Regardingtive. pharmacologic activity, N-oxides of all the reviewed drug cases are inactive. (3)(3) MetabolicallyMetabolically formedformed N-oxides-oxides of of drugs drugs may may revert revert to tothe the parent parent drugs drugs through through bio- bioreduction.reduction. TheThe structure structure of of the theN N-oxide-oxide group group and and its its representations representations are are shown shown in in Figure Figure 44 44..

Drug Drug + - Drug R NO R1 R2N O 2 N OR2

N-oxide group and its representations FigureFigure 44. 44.N-oxide N-oxide group group and and its its representations. representations.

NN-oxidation-oxidation is is a a common common metabolic metabolic pathway pathway of of most most drugs drugs containing containing aliphatic aliphatic and and heterocylicheterocylic tertiary tertiary alkylamino alkylamino moieties moieties [227 [227].]. All All the theN N-oxide-oxide metabolites metabolites of of the the reviewed reviewed drugdrug examplesare examplesare devoid devoid of of pharmacologic pharmacologic activity. activity. The The lack lack of of pharmacologic pharmacologic activity activity of of thetheN N-oxides-oxides is is a a result result of of the the masking masking of of the the potential potential cationic cationic charge charge of of the the amine, amine, which which abolishes its potential ability to interact with receptors through ionic bindings. In case the ionic binding of the amine is primary pharmacophoric, its loss should explains why N-oxides of drugs are inactive. Nevertheless, upon bioreduction of the N-oxide metabolite

to the tertiary-amino-moiety-containing drug, the amino group will resume its ability to be protonated (i.e., be ionized) at pH 7.4 and establish ionic binding essential for drug-receptor affinity and accordingly drug efficacy and activity. By being converted back to the active forms, the N-oxide metabolites of drugs have been suggested as bioreductive prodrugs [228–230]. The planning of N-oxides as prodrugs implies that the N-oxides are devoid of pharmacologic activity and need to be bioactivated by Flavin-containing monooxygenase (FMO) in vivo. In fact, some N-oxide prodrugs are currently marketed while others have been patented. The marketed N-oxide prodrugs are imipraminoxide (the N-oxide of imipramine [231], Figure3) and (the N-oxide of amitriptyline, Figure4)[ 232]. They are used for the treatment of depression; they have similar effects as well as equivalent efficacy to their active forms. The patented N-oxide prodrugs include: (i) Sildenafil-N-oxide, a prodrug of sildenafil, described in a patent for the treatment of erectile dysfunction and pulmonary arterial hypertension (PAH) [233]. (ii) Venlafaxine-N-oxide and O-desmethylvenlafaxine-N-oxide, both of which have been patented as prodrugs of venlafaxine and O-desmethylvenlafaxine, respectively, and are used in the treatment of depression [234]. (iii) Lidocaine (lignocaine) N-oxide used in the treatment of pulmonary inflammation associated with asthma, bronchitis, and chronic obstructive pulmonary disease (COPD) [235]. The N-oxide metabolites of the tertiary alkylamino drugs cited in this review form potential candidates for prodrug development with possible improved bioavailability and longer duration of action relative to the parent drugs. The N-oxide metabolites include clomipramine-N-oxide, doxepin-N-oxide, citalopram-N-oxide, clozapine-N-oxide, mirtazapine-N-oxide and olanzapine-N-oxide. Molecules 2021, 26, 1917 33 of 40

15. Conclusions Alkylamino moieties in drug molecules undergo two types of metabolic reactions: N- dealkylation and N-oxidation. The former metabolic change has resulted in clinically used drugs, potential drugs, activation of prodrugs as well as attenuation and loss of activity of drugs. The N-oxide metabolites resulting from N-oxidation of dialkylamino moieties are invariably pharmacologically inactive but are bioreducible to the active forms. As thus, they have formed and will form basis of prodrug development. The physicochemical changes that result from N-dealkylation and N-oxidation of alkylamino moieties explain the changes in the metabolites relative to the parent drugs regarding binding to receptors, affinity, efficacy and accordingly pharmacological activity. The information provided is of broad utility in structure-based drug design.

Funding: This research received no external funding. Acknowledgments: The author would like to thank the University of Science and Technology of Fujairah for allocating research hours to faculty. Conflicts of Interest: The author declares no conflict of interest.

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