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Minimal structural changes determine full and partial nicotinic receptor agonist activity for nicotine analogues

dc.contributor.authorGonzalez-Gutierrez J.P.
dc.contributor.authorHodar M.
dc.contributor.authorViscarra F.
dc.contributor.authorPaillali P.
dc.contributor.authorGuerra-Díaz N.
dc.contributor.authorPessoa-Mahana H.
dc.contributor.authorHernández-Morantes J.J.
dc.contributor.authorPérez-Sánchez H.
dc.contributor.authorBermúdez I.
dc.contributor.authorReyes-Parada M.
dc.contributor.authorIturriaga-Vásquez P.
dc.date.accessioned2020-09-02T22:19:21Z
dc.date.available2020-09-02T22:19:21Z
dc.date.issued2019
dc.identifier10.3390/molecules24152684
dc.identifier.citation24, 15, -
dc.identifier.issn14203049
dc.identifier.urihttps://hdl.handle.net/20.500.12728/4713
dc.descriptionNeuronal α4β2 nicotinic acetylcholine receptors (nAChRs) are ligand-gated ion channels (LGIC) that have been implicated in nicotine addiction, reward, cognition, pain disorders, anxiety, and depression. Nicotine has been widely used as a template for the synthesis of ligands that prefer α4β2 nAChRs subtypes. The most important therapeutic use for α4β2 nAChRs is as replacement therapy for smoking cessation and withdrawal and the most successful therapeutic ligands are partial agonists. In this case, we use the N-methylpyrrolidine moiety of nicotine to design and synthesize new α4β2 nicotinic derivatives, coupling the pyrrolidine moiety to an aromatic group by introducing an ether-bonded functionality. Meta-substituted phenolic derivatives were used for these goals. Radioligand binding assays were performed on clonal cell lines of hα4β2 nAChR and two electrode voltage-clamp experiments were used for functional assays. Molecular docking was performed in the open state of the nAChR in order to rationalize the agonist activity shown by our compounds. © 2019 by the authors.
dc.language.isoen
dc.publisherMDPI AG
dc.subjectDocking
dc.subjectPartial agonist
dc.subjectPyrrolidine ethers
dc.subjectα4β2 nAChR
dc.subjectnicotine
dc.subjectnicotinic agent
dc.subjectnicotinic receptor
dc.subjectprotein binding
dc.subjectbinding competition
dc.subjectchemical structure
dc.subjectchemistry
dc.subjectconformation
dc.subjectdose response
dc.subjecthuman
dc.subjectkinetics
dc.subjectmolecular docking
dc.subjectmolecular dynamics
dc.subjectstructure activity relation
dc.subjectBinding, Competitive
dc.subjectDose-Response Relationship, Drug
dc.subjectHumans
dc.subjectKinetics
dc.subjectMolecular Conformation
dc.subjectMolecular Docking Simulation
dc.subjectMolecular Dynamics Simulation
dc.subjectMolecular Structure
dc.subjectNicotine
dc.subjectNicotinic Agonists
dc.subjectProtein Binding
dc.subjectReceptors, Nicotinic
dc.subjectStructure-Activity Relationship
dc.titleMinimal structural changes determine full and partial nicotinic receptor agonist activity for nicotine analogues
dc.typeArticle


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