Synthesis, Nicotinic Acetylcholine Receptor Binding, and Antinociceptive Properties of 2-exo-2-(2‘-Substituted 5‘-pyridinyl)-7-azabicyclo[2.2.1]heptanes. Epibatidine Analogues

A convenient, high-yield synthesis of 7-tert-butoxycarbonyl-7-azabicyclo[2.2.1]hept-2-ene (<BO>5</BO>), which involved the addition of tributyltin hydride to 7-tert-butoxycarbonyl-2-p-toluenesulfonyl-7-azabicyclo[2.2.1]hept-2-ene (<BO>4</BO>) followed by elimination of the tributyltin and p-tolylsulfonyl groups using tetrabutylammonium fluoride was developed. The addition of 2-amino-5-iodopyridine to <BO>5</BO> under reductive Heck conditions provided 7-tert-butoxycarbonyl-2-exo-(2‘-amino-5‘-pyridinyl)-7-azabicyclo[2.2.1]heptane (<BO>6</BO>). Compound <BO>6</BO> was the key intermediate used to prepare epibatidine analogues where the 2‘-chloro group on the pyridine ring was replaced with a fluorine (<BO>1b</BO>), bromine (<BO>1c</BO>), iodine (<BO>1d</BO>), hydroxy (<BO>1e</BO>), amino (<BO>1f</BO>), dimethylamino (<BO>1g</BO>), trifluoromethanesulfonate (<BO>1h</BO>), and hydrogen (<BO>1i</BO>) group. (+)- and (−)-Epibatidine and compounds <BO>1b</BO>−<BO>d</BO> and <BO>1i</BO> all possess similar binding affinities at the α<INF>4</INF>β<INF>2</INF> nAChR receptors labeled by [³H]epibatidine. Compound <BO>1f</BO> has affinity similar to nicotine, whereas compounds <BO>1e</BO>, <BO>1g</BO>, and <BO>1h</BO> have much lower affinity. The binding affinity appears to be dependent upon the electronic nature of the substituent. However, other factors are also involved. None of the compounds possesses appreciable affinity for the α<INF>7</INF> nAChR labeled by [¹²⁵I]iodo-MLA. With the exception of <BO>1f</BO> and <BO>1g</BO>, all the epibatidine analogues are full agonists (tail flick test) in producing antinociception after intrathecal injection in mice.