Faundez-Parraguez_2013_Bioorg.Med.Chem_21_2687

Nicotine is an agonist of nicotinic acetylcholine receptors (nAChRs) that has been extensively used as a template for the synthesis of alpha4beta2-preferring nAChRs. Here, we used the N-methyl-pyrrolidine moiety of nicotine to design and synthesise novel alpha4beta2-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-(125)I]bungarotoxin to human alpha7 nAChRs and [(3)H]cytisine to human alpha4beta2 nAChRs, they were markedly more potent at displacing radioligand binding to human alpha4beta2 nAChRs than to alpha7 nAChRs. Functional assays showed that the neonicotinic compounds behave as antagonists at alpha4beta2 and alpha4beta2alpha5 nAChRs. Substitutions on the aromatic ring of the compounds produced compounds that displayed marked selectivity for alpha4beta2 or alpha4beta2alpha5 nAChRs. Docking of the compounds on homology models of the agonist binding site at the alpha4/beta2 subunit interfaces of alpha4beta2 nAChRs suggested the compounds inhibit function of this nAChR type by binding the agonist binding site.