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Please use this identifier to cite or link to this item: http://dspace.utalca.cl/handle/1950/9438

Title: Neonicotinic analogues: Selective antagonists for alpha 4 beta 2 nicotinic acetylcholine receptors
Authors: Faundez-Parraguez, M.
Farias-Rabelo, N.
Gonzalez-Gutierrez, J.P.
Etcheverry-Berrios, A.
Alzate-Morales, J.
Adasme-Carreno, F.
Varas, R.
Bermudez, I.
Iturriaga-Vasquez, P.
Keywords: Nicotinic acetylcholine receptors
Structure-activity relationships
Functional and affinities
Issue Date: 15-May-2013
Citation: Source: BIOORGANIC & MEDICINAL CHEMISTRY Volume: 21 Issue: 10 Pages: 2687-2694 DOI: 10.1016/j.bmc.2013.03.024
Abstract: Nicotine is an agonist of nicotinic acetylcholine receptors (nAChRs) that has been extensively used as a template for the synthesis of alpha 4 beta 2-preferring nAChRs. Here, we used the N-methyl-pyrrolidine moiety of nicotine to design and synthesise novel alpha 4 beta 2-preferring neonicotinic ligands. We increased the distance between the basic nitrogen and aromatic group of nicotine by introducing an ester functionality that also mimics acetylcholine (Fig. 2). Additionally, we introduced a benzyloxy group linked to the benzoyl moiety. Although the neonicotinic compounds fully inhibited binding of both [alpha-I-125]bungarotoxin to human alpha 7 nAChRs and [H-3]cytisine to human alpha 4 beta 2 nAChRs, they were markedly more potent at displacing radioligand binding to human alpha 4 beta 2 nAChRs than to alpha 7 nAChRs. Functional assays showed that the neonicotinic compounds behave as antagonists at alpha 4 beta 2 and alpha 4 beta 2 alpha 5 nAChRs. Substitutions on the aromatic ring of the compounds produced compounds that displayed marked selectivity for alpha 4 beta 2 or alpha 4 beta 2 alpha 5 nAChRs. Docking of the compounds on homology models of the agonist binding site at the alpha 4/beta 2 subunit interfaces of alpha 4 beta 2 nAChRs suggested the compounds inhibit function of this nAChR type by binding the agonist binding site. (C) 2013 Elsevier Ltd. All rights reserved.
Description: Alzate-Morales, J (Alzate-Morales, Jans) ; Adasme-Carreno, F (Adasme-Carreno, Francisco). Univ Talca, Ctr Bioinformat & Mol Simulat CBSM, Talca, Chile
URI: http://dspace.utalca.cl/handle/1950/9438
ISSN: 0968-0896
Appears in Collections:Artículos en publicaciones ISI - Universidad de Talca

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