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Synthesis of novel nicotinic ligands with multimodal action: Targeting Acetylcholine α4β2, Dopamine and Serotonin Transporters

dc.contributor.authorGonzález-Gutiérrez J.P.
dc.contributor.authorPessoa-Mahana H.A.
dc.contributor.authorIturriaga-Vásquez P.E.
dc.contributor.authorReyes-Parada M.I.
dc.contributor.authorGuerra-Díaz N.E.
dc.contributor.authorHodar-Salazar M.
dc.contributor.authorViscarra F.
dc.contributor.authorPaillali P.
dc.contributor.authorNúñez-Vivanco G.
dc.contributor.authorLorca-Carvajal M.A.
dc.contributor.authorMella-Raipán J.
dc.contributor.authorZúñiga M.C.
dc.date.accessioned2020-09-02T22:19:23Z
dc.date.available2020-09-02T22:19:23Z
dc.date.issued2019
dc.identifier10.3390/molecules24203808
dc.identifier.citation24, 20, -
dc.identifier.issn14203049
dc.identifier.urihttps://hdl.handle.net/20.500.12728/4724
dc.descriptionNicotinic acetylcholine receptors (nAChRs), serotonin transporters (SERT) and dopamine transporters (DAT) represent targets for the development of novel nicotinic derivatives acting as multiligands associated with different health conditions, such as depressive, anxiety and addiction disorders. In the present work, a series of functionalized esters structurally related to acetylcholine and nicotine were synthesized and pharmacologically assayed with respect to these targets. The synthesized compounds were studied in radioligand binding assays at α4β2 nAChR, h-SERT and h-DAT. SERT experiments showed not radioligand [3H]-paroxetine displacement, but rather an increase in the radioligand binding percentage at the central binding site was observed. Compound 20 showed Ki values of 1.008 ± 0.230 µM for h-DAT and 0.031 ± 0.006 µM for α4β2 nAChR, and [3H]-paroxetine binding of 191.50% in h-SERT displacement studies, being the only compound displaying triple affinity. Compound 21 displayed Ki values of 0.113 ± 0.037 µM for α4β2 nAChR and 0.075 ± 0.009 µM for h-DAT acting as a dual ligand. Molecular docking studies on homology models of α4β2 nAChR, h-DAT and h-SERT suggested potential interactions among the compounds and agonist binding site at the α4/β2 subunit interfaces of α4β2 nAChR, central binding site of h-DAT and allosteric modulator effect in h-SERT. © 2019 by the authors.
dc.language.isoen
dc.publisherMDPI AG
dc.subjectAffinity
dc.subjectAllosteric modulators
dc.subjectAllosteric modulators
dc.subjectDAT
dc.subjectNAChR
dc.subjectSERT
dc.subjectα4β2
dc.subjectacetylcholine
dc.subjectdopamine
dc.subjectdopamine receptor stimulating agent
dc.subjectdopamine transporter
dc.subjectester
dc.subjectligand
dc.subjectnicotine
dc.subjectnicotinic agent
dc.subjectnicotinic receptor
dc.subjectnicotinic receptor alpha4beta2
dc.subjectpyrrolidine
dc.subjectpyrrolidine derivative
dc.subjectserotonin transporter
dc.subjectallosterism
dc.subjectbinding site
dc.subjectchemistry
dc.subjectHEK293 cell line
dc.subjecthuman
dc.subjectmolecular docking
dc.subjectradioassay
dc.subjectstructure activity relation
dc.subjectsynthesis
dc.subjectAcetylcholine
dc.subjectAllosteric Regulation
dc.subjectBinding Sites
dc.subjectDopamine
dc.subjectDopamine Agonists
dc.subjectDopamine Plasma Membrane Transport Proteins
dc.subjectEsters
dc.subjectHEK293 Cells
dc.subjectHumans
dc.subjectLigands
dc.subjectMolecular Docking Simulation
dc.subjectNicotine
dc.subjectNicotinic Agonists
dc.subjectPyrrolidines
dc.subjectRadioligand Assay
dc.subjectReceptors, Nicotinic
dc.subjectSerotonin Plasma Membrane Transport Proteins
dc.subjectStructure-Activity Relationship
dc.titleSynthesis of novel nicotinic ligands with multimodal action: Targeting Acetylcholine α4β2, Dopamine and Serotonin Transporters
dc.typeArticle


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