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Distinctive Supramolecular Features of -Cyclodextrin Inclusion Complexes with Antidepressants Protriptyline and Maprotiline

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pharmaceuticals Article Distinctive Supramolecular Features of β-Cyclodextrin Inclusion Complexes with Antidepressants Protriptyline and Maprotiline: A Comprehensive Structural Investigation Thammarat Aree Department of Chemistry, Faculty of Science, Chulalongkorn University, Bangkok 10330, Thailand; [email protected]; Tel.: +66-2-2187584; Fax: +66-2-2187598 Abstract: Depression, a global mental illness, is worsened due to the coronavirus disease 2019 (COVID-2019) pandemic. Tricyclic antidepressants (TCAs) are efficacious for the treatment of de- pression, even though they have more side effects. Cyclodextrins (CDs) are powerful encapsulating agents for improving molecular stability, water solubility, and lessening the undesired effects of drugs. Because the atomic-level understanding of the β-CD–TCA inclusion complexes remains elusive, we carried out a comprehensive structural study via single-crystal X-ray diffraction and density functional theory (DFT) full-geometry optimization. Here, we focus on two complexes lining on the opposite side of the β-CD–TCA stability spectrum based on binding constants (Kas) in solution, β-CD–protriptyline (PRT) 1—most stable and β-CD–maprotiline (MPL) 2—least stable. X-ray crystal- lography unveiled that in the β-CD cavity, the PRT B-ring and MPL A-ring are aligned at a nearly perfect right angle against the O4 plane and primarily maintained in position by intermolecular C–H···π interactions. The increased rigidity of the tricyclic cores is arising from the PRT -CH=CH- bridge widens, and the MPL -CH –CH - flexure narrows the butterfly angles, facilitating the deepest Citation: Aree, T. Distinctive 2 2 β Supramolecular Features of and shallower insertions of PRT B-ring (1) and MPL A-ring (2) in the distorted round -CD cavity for β-Cyclodextrin Inclusion Complexes better complexation. This is indicated by the DFT-derived complex stabilization energies (DEstbs), with Antidepressants Protriptyline although the complex stability orders based on Kas and DEstbs are different. The dispersion and the and Maprotiline: A Comprehensive basis set superposition error (BSSE) corrections were considered to improve the DFT results. Plus, the Structural Investigation. distinctive 3D arrangements of 1 and 2 are discussed. This work provides the first crystallographic Pharmaceuticals 2021, 14, 812. evidence of PRT and MPL stabilized in the β-CD cavity, suggesting the potential application of CDs http://doi.org/10.3390/ph14080812 for efficient drug delivery. Academic Editor: Karolina Pytka Keywords: β-cyclodextrin; protriptyline; maprotiline; tricyclic antidepressants (TCAs); X-ray analy- sis; DFT calculation Received: 20 July 2021 Accepted: 16 August 2021 Published: 18 August 2021 1. Introduction Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in Depression is a serious mental illness as over 300 million people worldwide suffer published maps and institutional affil- from depression, and about 800,000 people die from suicide each year [1]. Due to the iations. emerging coronavirus disease 2019 (COVID-19), a critical question arises: to what extent does the COVID-19 pandemic worsen depression? Recent studies unveiled the alarming statistics: (i) 1.5-year since the COVID-19 outbreak, the number of confirmed COVID-19 cases has topped 170 million across the globe [2]; (ii) 23% of COVID-19 patients worldwide have depression symptoms in common [3]; and (iii) 50% of the survivors suffer from Copyright: © 2021 by the author. Licensee MDPI, Basel, Switzerland. depression [4]. Therefore, both the COVID-19 and its mental effect (depression) require This article is an open access article effective treatments concurrently. distributed under the terms and Tricyclic antidepressants (TCAs) are efficient second-line medications for the treatment ◦ conditions of the Creative Commons of depression. The widely used TCAs include the secondary (2 ) amine desipramine (DPM), ◦ Attribution (CC BY) license (https:// nortriptyline (NRT), and the tertiary (3 ) amine imipramine (IPM), amitriptyline (AMT), ◦ ◦ creativecommons.org/licenses/by/ clomipramine (CPM), doxepin (DXP), Scheme1. Although the 2 and 3 amine TCAs share 4.0/). similar structures, they interact differently with neurotransmitters, thus having distinct Pharmaceuticals 2021, 14, 812. https://doi.org/10.3390/ph14080812 https://www.mdpi.com/journal/pharmaceuticals Pharmaceuticals 2021, 14, x FOR PEER REVIEW 2 of 22 Pharmaceuticals 2021, 14, 812 (AMT), clomipramine (CPM), doxepin (DXP), Scheme 1. Although the 2° and 3° amine2 of 21 TCAs share similar structures, they interact differently with neurotransmitters, thus hav- ing distinct pharmacological effects. While the 2° amine TCAs selectively inhibit norepi- pharmacologicalnephrine, the 3° amine effects. TCAs While block the 2the◦ amine reuptake TCAs of both selectively norepinephrine inhibit norepinephrine, and serotonin the[5]. 3Protriptyline◦ amine TCAs (PRT; block Vivactil) the reuptake and ofmaprotiline both norepinephrine (MPL; Ludiomil) and serotonin are members [5]. Protriptyline of the 2° (PRT;amine Vivactil) TCAs, thus and favoring maprotiline norepinephrine (MPL; Ludiomil) over areserotonin. members Like of theall other 2◦ amine TCAs, TCAs, PRT thus and favoringMPL mostly norepinephrine share a common over serotonin.structural Likefeature all of other a butterfly TCAs, PRT with and the MPL aromatic mostly A and share B arings common as wings structural and the feature 3-C-length of a butterfly side-chain with asthe a tail. aromatic Their distinct A and B parts rings are as wingsthe central and theC-ring 3-C-length (Scheme side-chain 1). MPL with as a tail.a rigid Their flexure distinct arising parts from are thean ethylene central C-ring bridge (Scheme across 1the). MPLcentral with 6-membered a rigid flexure C-ring arising is also from categorized an ethylene as bridgean atypical, across tetracyclic the central antidepressant 6-membered C-ring(TeCA) is and also is categorized prescribed as as an the atypical, most select tetracyclicive noradrenaline antidepressant reuptake (TeCA) andinhibitor is prescribed (SNRI) as[6]. the PRT most is a selectiveclassic TCA noradrenaline with the central reuptake cycloheptatriene inhibitor (SNRI) ring (Scheme [6]. PRT 1). is aWhereas classic TCAMPL withcan cause the central drowsiness cycloheptatriene and dehydration, ring (Scheme PRT can1 ).cause Whereas heart MPLrhythm can problems cause drowsiness and affect andsex drive dehydration, [7]. Among PRT five can TCAs cause (PRT, heart rhythmAMT, MPL, problems DXP, andand affectNRT) sex exhibiting drive [7 ].inhibitory Among fiveactivity TCAs against (PRT, major AMT, MPL,Alzheimer’s DXP, and disease NRT) (AD) exhibiting targets, inhibitory PRT is the activity most againstpotent majormulti- Alzheimer’starget directed disease ligand (AD) for targets,AD treatment PRT is the[8], mostwhich potent has been multi-target clinically directed tested in ligand rats for[9]. ADVery treatment recent research [8], which indicates has been that clinically MPL has tested anticancer in rats activity [9]. Very against recent hepatocellular research indicates car- thatcinoma MPL cells has [10]. anticancer activity against hepatocellular carcinoma cells [10]. SchemeScheme 1.1. ChemicalChemical structuresstructures andand atomatom numberingnumbering schemesschemes ofof tricyclictricyclic antidepressantsantidepressants (TCAs;(TCAs; butterflybutterfly structure)structure) andand b-cyclodextrinb-cyclodextrin ((ββ-CD;-CD; conicalconical shape).shape). The six widely used TCAs areare the secondary amine DPM, NRT, andand thethe tertiarytertiary amineamine IPM,IPM, AMT,AMT, CPM,CPM,E E//Z-DXP. TheThe differentdifferent TCAs,TCAs, includingincluding PRTPRT andand MPL,MPL, ofof whichwhich theirtheir distinctdistinct structurestructure portionsportions are magenta highlighted. TCAs are commercially available in HCl salt form. Note the reflection symmetry of the (6-7-6)- are magenta highlighted. TCAs are commercially available in HCl salt form. Note the reflection symmetry of the (6-7- tricyclic core (wing-body-wing) through a vertical mirror plane bisecting the central 7-membered C-ring. Like other TCAs 6)-tricyclic core (wing-body-wing) through a vertical mirror plane bisecting the central 7-membered C-ring. Like other with a skeleton of the B-C-A-rings from left to right, the flexure and the D-rings are beneath the C-ring for the bicy- TCAsclo[2.2.2]octadiene with a skeleton backbone of the B-C-A-ringsof MPL. from left to right, the flexure and the D-rings are beneath the C-ring for the bicyclo[2.2.2]octadiene backbone of MPL. Cyclodextrins (CDs) are the most versatile encapsulating agents because they have a Cyclodextrins (CDs) are the most versatile encapsulating agents because they have a broad application spectrum, including pharmaceutics, cosmetics, medicine, food, agricul- broad application spectrum, including pharmaceutics, cosmetics, medicine, food, agricul- ture, chromatography, biotechnology, and nanotechnology [11–14]. The excellent inclusion ability of CDs is attributed to their amphipathic character and nanocavity size, stabilizing and interacting intermolecularly with various guest molecules [15,16]. CDs adopt a shape of hollow, truncated cone with a height of ~8 Å (distance of two hydrophilic rims; wider O2– Pharmaceuticals 2021, 14, x FOR PEER REVIEW 3 of 22 ture, chromatography, biotechnology, and nanotechnology [11–14]. The excellent inclu- sion ability of CDs is attributed to their amphipathic character and nanocavity size,
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