%0 Journal Article %1 RN130 %A Faundez-Parraguez, M. %A Farias-Rabelo, N. %A Gonzalez-Gutierrez, J.P. %A Etcheverry-Berrios, A. %A Alzate-Morales, J. %A Adasme-Carreno, F. %A Varas, R. %A Bermudez, I. %A Iturriaga-Vasquez, P. %D 2013 %I 2013 Elsevier Ltd. %J Bioorganic & Medicinal Chemistry %K acetylcholine affinities, agonists, and antagonism, beta-2 binding, cytisine, docking dqcauchile functional modulators, nicotinic receptors, relationships, sensitivity, structure-activity subunit, %N 10 %P 2687-2694 %R 10.1016/j.bmc.2013.03.024 %T Neonicotinic Analogues: Selective Antagonists for Alpha 4 Beta 2 Nicotinic Acetylcholine Receptors %U /brokenurl#<Go to ISI>://WOS:000318318700003 %V 21 %X 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-125bungarotoxin to human alpha 7 nAChRs and H-3cytisine 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.

@article{RN130, 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. }, added-at = {2019-12-04T03:57:35.000+0100}, author = {Faundez-Parraguez, M. and Farias-Rabelo, N. and Gonzalez-Gutierrez, J.P. and Etcheverry-Berrios, A. and Alzate-Morales, J. and Adasme-Carreno, F. and Varas, R. and Bermudez, I. and Iturriaga-Vasquez, P.}, biburl = {https://www.bibsonomy.org/bibtex/2453273b56e1bc92b375ec76ed224b827/dqcauchile}, doi = {10.1016/j.bmc.2013.03.024}, interhash = {687fdb7a374c953d5886b4f7c87b7f9d}, intrahash = {453273b56e1bc92b375ec76ed224b827}, issn = {0968-0896}, journal = {Bioorganic & Medicinal Chemistry}, keywords = {acetylcholine affinities, agonists, and antagonism, beta-2 binding, cytisine, docking dqcauchile functional modulators, nicotinic receptors, relationships, sensitivity, structure-activity subunit,}, number = 10, pages = {2687-2694}, publisher = {2013 Elsevier Ltd.}, timestamp = {2019-12-04T03:58:17.000+0100}, title = {Neonicotinic Analogues: Selective Antagonists for Alpha 4 Beta 2 Nicotinic Acetylcholine Receptors}, type = {Journal Article}, url = {/brokenurl#<Go to ISI>://WOS:000318318700003}, volume = 21, year = 2013 }