Synthesis and Pharmacological Characterization of Nicotinic Acetylcholine Receptor Properties of (+)- and (−)-Pyrido-[3,4-b]homotropanes

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 potent activity 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 synthesis of (+)- and (-)-1 and show that (+)-1 has Ki = 1.29 nM at the alpha4beta2* nAChR and has over 260 times higher affinity than (-)-1. Single-crystal X-ray analysis of an intermediate used to prepare the isomers established the absolute stereochemistry as (1S,6S)-(+)-1 and (1R,6R)-(-)-1. Surprisingly, both isomers failed to produce antinociception in the mouse tail-flick and hot-plate assays, engender nicotine-like responding in rat drug discrimination, or alter current amplitude in alpha4beta2- and alpha3beta4-containing cells. However, (-)-1 antagonized nicotine-induced antinociception with an ED50 of 0.07 microg/kg in the tail-flick assay. The reason for 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.