A series of 3'-substituted deschloroepibatidine analogues (3a-g and 4) showed high affinity for alpha4beta2 binding and relatively weak affinity for alpha7 nAChRs. The 3'-ethynyl (3g) and X-fluoro (3a) analogues with K-i values of 0.02 and 0.037 nM, respectively, were the most potent. Even though the alpha4beta2 binding affinity of several of the analogues were equal to that of epibatidine, all of the compounds were weak agonists in the antinociceptive, hypothermia, and spontaneous activity test in mice. In contrast, all of the compounds were functional antagonists of nicotine-induced antinociception. In general, compounds 3a-g and 4 were more potent in the tail-flick assay than the hot-plate test. For example, the X-fluoro analogue 3a and the N-methyl-3'-iodo analogue 4 showed AD(50) values of 0.07 and 0.04 mug/kg, respectively, in the tail flick test and only 35 and 0% inhibition at 20 and 10 mug/kg in the hot-plate assay, respectively. These results suggest that these compounds will be highly useful for identifying which specific receptor subtypes are involved in each of nicotine's pharmacological effects. The high affinity of the N-methyl-3'-iodo analogue 4 combined with its weak agonist and potent antagonist activity suggests that carbon-11 and iodine-123 analogues may be useful as PET and SPECT ligands, respectively, for studying nAChRs in vivo
Synthesis, nicotinic acetylcholine receptor binding, and antinociceptive properties of 3 '-substituted deschloroepibatidine analogues. Novel nicotinic antagonists
Carroll, F., Ma, W., Yokota, Y., Lee, J., Brieaddy, L., Navarro, H., ... Martin, BR. (2005). Synthesis, nicotinic acetylcholine receptor binding, and antinociceptive properties of 3 '-substituted deschloroepibatidine analogues. Novel nicotinic antagonists. Journal of Medicinal Chemistry, 48(4), 1221-1228.