Ondachi_2012_J.Med.Chem_55_6512

Herein, we report the synthesis and nicotinic acetylcholine receptor (nAChR) in vitro and in vivo pharmacological properties of 2'-fluoro-3'-(substituted phenyl)deschloroepibatidines 5b-g, analogues of 3'-(4-nitrophenyl) compound 5a. All compounds had high affinity for alpha4beta2-nAChR and low affinity for alpha7-nAChR. Initial electrophysiological studies showed that all analogues were antagonists at alpha4beta2-, alpha3beta4-, and alpha7-nAChRs. The 4-carbamoylphenyl analogue 5g was highly selective for alpha4beta2-nAChR over alpha3beta4- and alpha7-nAChRs. All the analogues were antagonists of nicotine-induced antinociception in the tail-flick test. Molecular modeling docking studies using the agonist-bound form of the X-ray crystal structure of the acetylcholine binding protein suggested several different binding modes for epibatidine, varenicline, and 5a-g. In particular, a unique binding mode for 5g was suggested by these docking simulations. The high binding affinity, in vitro efficacy, and selectivity of 5g for alpha4beta2-nAChR combined with its nAChR functional antagonist properties suggest that 5g will be a valuable pharmacological tool for studying the nAChR and may have potential as a pharmacotherapy for addiction and other central nervous system disorders.