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 phenyl)­deschloroepibatidines <b>5b</b>–<b>g</b>, analogues of 3′-(4-nitrophenyl) compound <b>5a</b>. All compounds had high affinity for α4β2-nAChR and low affinity for α7-nAChR. Initial electrophysiological studies showed that all analogues were antagonists at α4β2-, α3β4-, and α7-nAChRs. The 4-carbamoylphenyl analogue <b>5g</b> was highly selective for α4β2-nAChR over α3β4- and α7-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 <b>5a</b>–<b>g</b>. In particular, a unique binding mode for <b>5g</b> was suggested by these docking simulations. The high binding affinity, in vitro efficacy, and selectivity of <b>5g</b> for α4β2-nAChR combined with its nAChR functional antagonist properties suggest that <b>5g</b> 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