Synthesis and Electrophysiological Studies of a Novel Epibatidine Analogue

Abstract

The new epibatidine analogue exo-2-(2-pyridyl)-7-azabicyclo[2.2.1]heptane (2PABH) was synthesised. Separation of enantiomers was performed on chiral HPLC chromatography in polar-organic phase mode at 0°C. Enantiomeric purity was greater than 99.8%ee for the (-)- and 90.5%ee for the (+)-enantiomer respectively. Optical rotation was determined to be [α]_D²³ = ±13°. Electrophysiological studies of 2PABH were carried out on α4β2. α3β4 and α7 nAChR subtypes cloned from rat and reconstituted in Xenopus oocytes. Both enantiomers could not significantly activate the heteromeric subtypes. The homomeric α7 nAChR displays a high sensitivity only towards (-)-2PABH. The EC₅₀ for (-)-2PABH and ACh were determined (32.5 ± 9.5μM, 137.3 ± 16.5μM). (-)-2PABH was shown to be a partial agonist (80% of ACh). Thus the efficacy of 2PABH differs markedly from that of epibatidine. The intramolecular N-N-distance and the spatial pyridine nitrogen orientation play a central role in nAChR recognition.