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 (5), which involved the addition of tributyltin hydride to 7 -tert-butoxycarbonyl-2-p-toluenesulfonyl-7-azabicyclo[2.2.1]hept-2-ene (4) followed by elimination of the tributyltin and p-tolylsulfonyl groups using tetrabutylammonium fluoride was developed. The addition of 2-amino-5-iodop yridine to 5 under reductive. Heck conditions provided 7-tert-butoxycarbony l-2-exo-(2 ' -amino-5 ' -pyridinyl)-7-azabicyclo [2.2.1]heptane (6). Compou nd 6 was the key intermediate used to prepare epibatidine analogues where t he 2 ' -chloro group on the pyridine ring was replaced with a fluorine (Ib) , bromine (1c), iodine (1d), hydroxy (1e), amino (1f), dimethylamino (1g), trifluoromethanesulfonate (1h), and hydrogen (1i) group. (+)- and (-)-Epiba tidine and compounds 1b-d and Ii all possess similar binding affinities at the alpha (4)beta (2) nAChR receptors labeled by [H-3]epibatidine. Compound If has affinity similar to nicotine, whereas compounds le, Ig, and Ih have much lower affinity. The binding affinity appears to be dependent upon the electronic nature of the substituent. However, other factors are also invo lved. None of the compounds possesses appreciable affinity for the alpha (7 ) nAChR labeled by [I-125]iodo-MLA. With the exception of If and Ig, all th e epibatidine analogues are full agonists (tail flick test) in producing an tinociception after intrathecal injection in mice.