| Abstract
| - A series of 3‘-substituted deschloroepibatidine analogues (3a−g and 4) showed high affinityfor α4β2 binding and relatively weak affinity for α7 nAChRs. The 3‘-ethynyl (3g) and 3‘-fluoro(3a) analogues with Ki values of 0.02 and 0.037 nM, respectively, were the most potent. Eventhough the α4β2 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 spontaneousactivity 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-flickassay than the hot-plate test. For example, the 3‘-fluoro analogue 3a and the N-methyl-3‘-iodoanalogue 4 showed AD50 values of 0.07 and 0.04 μg/kg, respectively, in the tail flick test andonly 35 and 0% inhibition at 20 and 10 μg/kg in the hot-plate assay, respectively. These resultssuggest that these compounds will be highly useful for identifying which specific receptorsubtypes are involved in each of nicotine's pharmacological effects. The high affinity of theN-methyl-3‘-iodo analogue 4 combined with its weak agonist and potent antagonist activitysuggests that carbon-11 and iodine-123 analogues may be useful as PET and SPECT ligands,respectively, for studying nAChRs in vivo.
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