Hexahydroquinoline Featuring Amide Functionality: A Promising Scaffold With Calcium Channel Blocking Activity

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dc.contributor.authorKocak Aslan, Ebru
dc.contributor.authorLam, Kevin
dc.contributor.authorHuang, Sun
dc.contributor.authorCoskun, Goknil Pelin
dc.contributor.authorKaraguzel, Ayse
dc.contributor.authorDenzinger, Katrin
dc.contributor.authorBirgul, Kaan
dc.date.accessioned2026-04-25T14:19:44Z
dc.date.available2026-04-25T14:19:44Z
dc.date.issued2026
dc.departmentSinop Üniversitesi
dc.description.abstractHexahydroquinoline (HHQ) is a widely recognized scaffold that has garnered considerable attention owing to its diverse pharmacological properties. The structure of HHQ includes a 1,4-dihydropyridine (DHP) ring, which serves as the pharmacophore for the predominant class of drugs known as calcium channel blockers. DHPs are frequently utilized in the management of cardiovascular diseases and also show potential for pain management. Since all DHPs on the market possess ester functionality, we aimed to employ bioisosteric replacement to observe if their amide-containing counterparts would still block calcium channels. Therefore, we synthesized new HHQs with ester or amide functionality (EM1-EM15) and investigated their effects on L-(Cav1.2) and T-(Cav3.2)-type calcium channels using the whole-cell patch clamp technique. Although the amide derivatives were somewhat less effective than their ester counterparts, they still blocked calcium channels to a significant degree. Retesting EM4 enantiomers on two types of calcium channels demonstrated that the (R)-isomer was more responsible for the blocking activity in both cases. Molecular docking and molecular dynamics simulations demonstrated that ( R )-EM4 and ( R )-EM6 adopt binding modes in Cav1.2 similar to amlodipine, while showing favorable stability. Docking studies in Cav3.2 suggested that EM compounds bind within the III-IV fenestration, a reported non-selective DHP binding site. Furthermore, amide derivatives were found to be more metabolically stable based on the in vitro experiments conducted on rat microsomes. Overall, our study reveals HHQ with an amide group as a promising new scaffold for developing future calcium channel blockers for treating cardiovascular and pain conditions.
dc.description.sponsorshipNatural Sciences and Engineering Research Council of Canada; Hacettepe University Scientific Research Projects Coordination Unit [THD-2024-21388]
dc.description.sponsorshipThe authors acknowledge the Scientific and Technological Research Application and Research Center, Sinop University, Turkey, for the use of the Bruker D8 QUEST diffractometer. A.K. gratefully acknowledges the financial support provided by The Scientific and Technological Research Council of Turkiye (TUB & Idot;TAK) through the 2211-A National PhD Scholarship Program. M.G.G, E.K.A., and A.K. would like to thank Hacettepe University Scientific Research Projects Coordination Unit for the financial support provided through Project THD-2024-21388. G.W.Z. acknowledges the financial support of Natural Sciences and Engineering Research Council of Canada. We gratefully acknowledge the separation work by Siddharth Jaya Sajeevan J and Reza Salehi of the University of Texas at Arlington.
dc.identifier.doi10.1002/ddr.70261
dc.identifier.issn0272-4391
dc.identifier.issn1098-2299
dc.identifier.issue2
dc.identifier.pmid41832946
dc.identifier.scopus2-s2.0-105032835338
dc.identifier.scopusqualityQ2
dc.identifier.urihttps://doi.org/10.1002/ddr.70261
dc.identifier.urihttps://hdl.handle.net/11486/8130
dc.identifier.volume87
dc.identifier.wosWOS:001715343900001
dc.identifier.wosqualityQ1
dc.indekslendigikaynakWeb of Science
dc.indekslendigikaynakScopus
dc.indekslendigikaynakPubMed
dc.language.isoen
dc.publisherWiley
dc.relation.ispartofDrug Development Research
dc.relation.publicationcategoryMakale - Uluslararası Hakemli Dergi - Kurum Öğretim Elemanı
dc.rightsinfo:eu-repo/semantics/openAccess
dc.snmzKA_WOS_20260420
dc.subjectdihydropyridine
dc.subjectenantioseparation
dc.subjectHantzsch synthesis
dc.subjectmetabolic stability
dc.subjectmolecular modeling
dc.subjectpatch clamp
dc.titleHexahydroquinoline Featuring Amide Functionality: A Promising Scaffold With Calcium Channel Blocking Activity
dc.typeArticle

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