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Adrenergic Blockers in Regard to Their Stereochemistry

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Adrenergic Blockers in Regard to Their Stereochemistry applied sciences Review Survey of Pharmacological Activity and Pharmacokinetics of Selected β-Adrenergic Blockers in Regard to Their Stereochemistry Ružena Cižmˇ áriková, Ladislav Habala *, Jindra Valentová and Mário Markuliak Department of Chemical Theory of Drugs, Faculty of Pharmacy, Comenius University Bratislava, SK-832 32 Bratislava, Slovakia; [email protected] (R.C.);ˇ [email protected] (J.V.); [email protected] (M.M.) * Correspondence: [email protected] Received: 18 January 2019; Accepted: 8 February 2019; Published: 13 February 2019 Abstract: The present survey concentrates on pharmacodynamics and pharmacokinetics of selected β-adrenergic blockers from the point of view of their stereochemistry. It could be shown that the activity in the arylaminoethanol and aryloxyaminopropanol group of β-blockers is higher in their (–)-enantiomers as compared with the (+)-enantiomers. The stereoisomers differ also in other types of bioactivity as well as in toxicity. The particular pharmacokinetic stages such as resorption, distribution, and metabolism are discussed in regard to their stereochemistry. Keywords: beta-blockers; stereochemistry; pharmacodynamics; pharmacokinetics 1. Introduction β-blockers have been used as drugs for more than 50 years in the therapy of several diseases of the cardiovascular system [1] as well as in other disorders connected with an increase in sympathetic tone, such as glaucoma [2,3], anxiety [4], thyrotoxicosis [5], osteoporosis [6], and migraine prophylaxis [7]. The study of this drug group is substantiated by high incidence rate of cardiovascular diseases [8], such as ischemic heart disease, hypertension [9–12], heart arrhythmia, hypertrophic cardiomyopathy [13], and heart failure [8,14], all of which have been brought into connection with β-adrenergic receptors. These disorders are among the main mortality causes and at present affect increasingly younger fractions of population. The particular β-blockers differ in the extent of preferential binding to β1-adrenergic receptors, that is, in their cardioselectivity, the extent of antagonist activity toward β-receptors, pharmacokinetic properties, and the presence or absence of intrinsic sympathomimetic activity (ISA). These properties further determine the differences in side effects and potential contraindications. β-blockers may be classified according to their pharmacodynamics, pharmacokinetics or duration of action [15]. They are usually categorized into following groups: A. Cardioselective β-adrenolytics without ISA. They affect mainly β1-receptors, while β2-receptors are blocked only at higher doses. The examples include atenolol, betaxolol, bisoprolol, esmolol, metoprolol, and nebivolol. B. Cardioselective β-adrenolytics with ISA. Because of their agonist activity they are sometimes called β-adrenolytics with vasodilatant effect. Typical members of this group are acebutolol and celiprolol. Appl. Sci. 2019, 9, 625; doi:10.3390/app9040625 www.mdpi.com/journal/applsci Appl. Sci. 2019, 9, 625 2 of 21 C. Non-selective β-adrenolytics without ISA. They act on both subtypes (β1 and β2) of β-adrenergic receptors. Metipranolol, nadolol, propranolol, sotanol, and timolol belong to this group. D. Non-selective β-adrenolytics with ISA. In addition to the blocking of β-receptors they also exert partial agonist activity. ISA causes minor reduction of bradycardia and cardiac output. Examples are bopindolol and pindolol. Appl. Sci. 2019, 9, x FOR PEER REVIEW 2 of 21 E. β-adrenolytics blocking simultaneously α- and β-receptors. In addition to the blocking of β-receptors they also exert partial agonist activity. ISA causes Apart from β-receptors they act partly also on α-receptors. Carvedilol and labetalol belong to minor reduction of bradycardia and cardiac output. Examples are bopindolol and pindolol. this group. E. β-adrenolytics blocking simultaneously α- and β-receptors. F. ApartLipophilic from ββ-adrenolytics.-receptors they act partly also on α-receptors. Carvedilol and labetalol belong to this group. F. LipophilicThey are better β-adrenolytics. metabolized in the liver and exhibit improved resorption and penetration of the blood-brainThey are barrier, better metabolized thus lowering in the the incidence liver and ofex suddenhibit improved heart failure. resorption and penetration of the blood-brain barrier, thus lowering the incidence of sudden heart failure. G. Hydrophilic β-adrenolytics. G. Hydrophilic β-adrenolytics. TheseThese drugs drugs do do not not penetrate penetrate the the central central nervous nervous system system (CNS). (CNS). They They are are to to a a greater greater degree degree capablecapable of of binding binding to to plasma plasma protei proteinsns and and are are eliminated eliminated renally renally [16]. [16]. 2.2. Chirality Chirality of of ββ-Blockers-Blockers ββ-adrenergic-adrenergic blockers blockers are are among among the the first first categories categories of of drugs drugs investigated investigated for for their their chiral chiral aspects. aspects. TheyThey contain contain one one or or several several stereogenic stereogenic centers centers in th ineir their structure structure and thus and thusare able are to able rotate to rotatethe plane the ofplane polarization of polarization of linearly of linearlypolarized polarized light either light to the either left to(‒)the or to left the (–) right or to(+). the In older right literature (+). In older we canliterature also find we the can terms also findlaevo the(l) and terms dextrolaevo (d)(l) to and describedextro the(d) direction to describe of therotation direction of polarized of rotation light. of Thepolarized spatial light. arrangement The spatial of arrangementsubstituents around of substituents the stereogenic around thecenter, stereogenic for example center, the for so-called example absolutethe so-called configuration, absolute configuration, can be described can be with described the help with of the the help Cahn-Ingold-Prelog of the Cahn-Ingold-Prelog (CIP) system (CIP) [17,18].system According [17,18]. According to their tochemical their chemical structure structure these thesedrugs drugs can be can classified be classified as arylaminoethanols as arylaminoethanols or aryloxyaminopropanolsor aryloxyaminopropanols (Fig (Figureure 1). 1In). both In both groups groups the themore more active active isomers isomers pertaining pertaining to their to their β- adrenolyticβ-adrenolytic activity activity are are the the (‒)-isomers (–)-isomers which which can can be be attributed attributed the the (R (R)-configuration)-configuration for for the the arylaminoethanolarylaminoethanol group group and and ( (SS)) for for the the aryloxyaminopropanol aryloxyaminopropanol group. group. Figure 1. Figure 1. StructureStructure and and stereochemistry stereochemistry of arylaminoetanolsof arylaminoetanols (left) (left) and aryloxyaminopropanolsand aryloxyaminopropanols (right). (right). The understanding of the chiral aspects of β-blockers in connection with their pharmacodynamic and pharmacokinetic properties is essential for achieving the optimum therapeutic effect. The understanding of the chiral aspects of β-blockers in connection with their pharmacodynamic The differences in pharmacodynamic and pharmacokinetic properties of the optical antipodes and pharmacokinetic properties is essential for achieving the optimum therapeutic effect. are determined by their specific interactions with chiral biomolecules, such as proteins involved in The differences in pharmacodynamic and pharmacokinetic properties of the optical antipodes the active membrane transport, blood plasma proteins, enzymes involved in metabolic processes, etc. are determined by their specific interactions with chiral biomolecules, such as proteins involved in A three-point model can be used for explanation of differences in the behavior of enantiomers regarding the active membrane transport, blood plasma proteins, enzymes involved in metabolic processes, etc. their interaction with the receptors. The more active stereoisomer forms three complementary binding A three-point model can be used for explanation of differences in the behavior of enantiomers interactions with the active site of the receptor while the less active stereoisomer is capable of regarding their interaction with the receptors. The more active stereoisomer forms three complementary binding interactions with the active site of the receptor while the less active stereoisomer is capable of forming only two binding interactions. The molecules of β-blockers generally utilize the aromatic ring, the amino and hydroxy groups to affect the binding to the receptor. To distinguish between the different pharmacological activities of the two enantiomers, Lehmann and Ariens [19–21] applied the designation eutomer to the desirable, more active enantiomer, whereas the designation distomer applies to the less favorable enantiomer (in terms of activity and/or toxicity). This classification is related to a specific kind of bioactivity, thus a distomer may be considered a eutomer in different type of pharmacological application. In the therapeutic practice the β-blockers have mostly been used in the form of their racemates, with the exception of penbutolol, timolol, atenolol, and levobunolol which are used as pure enantiomers [22]. To evaluate the impact of stereochemistry on the bioactivity of β-blockers, new Appl. Sci. 2019, 9, 625 3 of 21 forming only two binding interactions. The molecules of β-blockers generally utilize the aromatic
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