Neonicotinic analogues: Selective antagonists for a4b2 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 a4b2-prefer ring nAChRs.Here,we used the N-methyl-pyrrolidine moiety of nicotine to design and synthesise novel a4b2-preferring neonicotinic ligands. We increased the dis- tance between the basic nitrogen and aromatic group of nicotine by introducing an ester functionality that also mimics acetylcholine (Fig. 2). Additionally,we introduced abenzyloxy group linked to the ben- zoyl moiety. Although the neonicotinic compounds fully inhibited binding of both [a-125I]bungarotoxin to human a7 nAChRs and [3H]cytisine to human a4b2 nAChRs,they were markedly more potent at displacing radioligand bindi ng to human a4b2 nAChRs than to a7 nAChRs.Functional assays showed that the neonicotinic compounds behave as antagonists at a4b2 and a4b2a5 nAChRs.Substitutions on the aromatic ring of the compounds produced compounds that displayed marked selectivity for a4b2 or a4b2a5 nAChRs.Docking of the compounds on homology models of the agonist binding site at the a4/b2 subunit interfaces of a4b2 nAChRs suggested the compounds inhibit function of this nAChR type by binding the agonist binding site.