Synthesis, nicotinic acetylcholine receptor binding, and antinociceptive properties of 2-exo-2-(2 ',3 '-disubstituted 5 '-pyridinyl)-7-azabicyclo[2.2.]heptanes: Epibatidine analogues
A number of 2',3'-disubstituted epibatidine analogues were synthesized and evaluated in vitro for potency at nicotinic acetylcholine, receptors (nAChRs) and in vivo for antinociception activity in the tail-flick and hot-plate models of acute pain and for their ability to affect core body temperature. Compounds that possessed electron-withdrawing groups (F, Cl, Br, and I) in both the 2'- and the X-positions showed affinities at the nAChR similar to epibatidine. However, in vivo efficacy did not correlate with affinity. 2-exo-(3'-Amino-2'-chloro-5'-pyridinyl)-7-azabicyclo[2.2.1]heptane (2i), an epibatidine analogue possessing an electron-releasing amino group in the T-position, produced the highest affinity. Compound 2i was also the most selective epibatidine analogue with a K-i of 0.001 nM at alphabeta nAChRs, which is 26 times greater than that of epibatidine, and a alphabeta/alpha(7) K-i ratio of 14 000, twice that of epibatidine. In vivo testing revealed that this compound potently inhibited nicotine-induced antinociception with AD(50) values below 1 mug/kg. Surprisingly, this same compound was also an agonist at higher doses (ED(50)similar to20 mug/kg). Thus, the addition of the X-amino group to epibatidine confers potent antagonist activity to the compound with little effect on agonist activity. 2,3-Disubstituted epibatidine analogues possessing a 2'-amino group combined with a X-bromo or X-iodo group showed in vitro and in vivo nAChR properties similar to nicotine.
Carroll, F., Lee, J., Navarro, H., Ma, W., Brieaddy, L., Abraham, P., ... Martin, B. R. (2002). Synthesis, nicotinic acetylcholine receptor binding, and antinociceptive properties of 2-exo-2-(2 ',3 '-disubstituted 5 '-pyridinyl)-7-azabicyclo[2.2.]heptanes: Epibatidine analogues. Journal of Medicinal Chemistry, 45(21), 4755-4761.