Neonicotinic analogues: Selective antagonists for alpha 4 beta 2 nicotinic acetylcholine receptors

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.