Synthesis and Nicotinic Acetylcholine Receptor in Vitro and in Vivo Pharmacological Properties of 2′-Fluoro-3′-(substituted phenyl)deschloroepibatidine Analogues of 2′-Fluoro-3′-(4-nitrophenyl)deschloroepibatidine

Herein, we report the synthesis and nicotinic acetylcholine receptor (nAChR) in vitro and in vivo pharmacological properties of 2'-fluoro-3'-(substituted phenyOdeschloroepibatidines 5b-g, analogues of 3'-(4-nitrophenyl) compound Sa. All compounds had high affinity for alpha 4 beta 2-nAChR and low affinity for alpha 7-nAChR. Initial electrophysiological studies showed that all analogues were antagonists at alpha 4 beta 2-, alpha 3 beta 4-, and alpha 7-nAChRs. The 4-carbamoylphenyl analogue 5g was highly selective for alpha 4 beta 2-nAChR over alpha 3 beta 4- and alpha 7-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 alpha 4 beta 2-nAChR combined with its nAChR functional antagonist properties suggest that Sg will be a valuable pharmacological tool for studying the nAChR and may have potential as a phamiacotherapy for addiction and other central nervous system disorders.