| Abstract
| - (±)-Pyrido[3,4-b]homotropane [(±)-1] is a conformationally rigid analogue of nicotine (2) or nornicotine(3) that showed high affinity for nicotinic acetylcholine receptors. Even though the synthesis and potentactivity of this highly interesting compound was originally reported in 1986 (Kanne, D. B.; Ashworth, D.J.; Cheng, M. T.; Mutter, L. C.; Abood, L. G. Synthesis of the first highly potent bridged nicotinoid.9-Azabicylo[4.2.l]nona[2,3-c]pyridine (pyrido[3,4-b]homotropane). J. Am. Chem. Soc.1986, 108, 7864−7865), the individual optical isomers have not been prepared and studied. In this study, we report the synthesisof (+)- and (−)-1 and show that (+)-1 has Ki = 1.29 nM at the α4β2* nAChR and has over 260 timeshigher affinity than (−)-1. Single-crystal X-ray analysis of an intermediate used to prepare the isomersestablished the absolute stereochemistry as (1S,6S)-(+)-1 and (1R,6R)-(−)-1. Surprisingly, both isomersfailed to produce antinociception in the mouse tail-flick and hot-plate assays, engender nicotine-like respondingin rat drug discrimination, or alter current amplitude in α4β2- and α3β4-containing cells. However, (−)-1antagonized nicotine-induced antinociception with an ED50 of 0.07 μg/kg in the tail-flick assay. The reasonfor this unusual pharmacology is unknown, but it is possible that (−)-1 is acting at a non-epibatidine-sensitive receptor subtype to antagonize nicotine's effects in the tail-flick assay.
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