2013 |
Faundez-Parraguez, M; Farias-Rabelo, N; González-Gutierrez, J P; Etcheverry-Berrios, A; Alzate-Morales, J; Adasme-Carreno, F; Varas, R; Bermudez, I; Iturriaga-Vasquez, P Neonicotinic Analogues: Selective Antagonists for Alpha 4 Beta 2 Nicotinic Acetylcholine Receptors Artículo de revista Bioorganic & Medicinal Chemistry, 21 (10), pp. 2687-2694, 2013, ISSN: 0968-0896. Resumen | Enlaces | BibTeX | Etiquetas: agonists, and antagonism, beta-2 binding, cytisine, docking functional modulators, nicotinic receptors, relationships, sensitivity, structure-activity subunit @article{RN130, title = {Neonicotinic Analogues: Selective Antagonists for Alpha 4 Beta 2 Nicotinic Acetylcholine Receptors}, author = { M. Faundez-Parraguez and N. Farias-Rabelo and J.P. Gonz\'{a}lez-Gutierrez and A. Etcheverry-Berrios and J. Alzate-Morales and F. Adasme-Carreno and R. Varas and I. Bermudez and P. Iturriaga-Vasquez}, url = {/brokenurl#<Go to ISI>://WOS:000318318700003}, doi = {10.1016/j.bmc.2013.03.024}, issn = {0968-0896}, year = {2013}, date = {2013-01-01}, journal = {Bioorganic & Medicinal Chemistry}, volume = {21}, number = {10}, pages = {2687-2694}, publisher = {2013 Elsevier Ltd.}, 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.}, keywords = {agonists, and antagonism, beta-2 binding, cytisine, docking functional modulators, nicotinic receptors, relationships, sensitivity, structure-activity subunit}, pubstate = {published}, tppubtype = {article} } 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. |
2013 |
Neonicotinic Analogues: Selective Antagonists for Alpha 4 Beta 2 Nicotinic Acetylcholine Receptors Artículo de revista Bioorganic & Medicinal Chemistry, 21 (10), pp. 2687-2694, 2013, ISSN: 0968-0896. |