Synthesis, nicotinic acetylcholine receptor binding, and antinociceptive properties of 2-exo-2-(2 ',3 '-disubstituted 5 '-pyridinyl)-7-azabicyclo[2.2.]heptanes: Epibatidine analogues
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.
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.