Synthesis and electrophysiological studies of a novel epibatidine analogue

The new epibatidine analogue exo-2-(2-pyridyl)-7-azabicyclo[2.2.1]hep (2PAB H) was synthesised. Separation of enantiomers was performed on chiral HPLC chromatography in polar-organic phase mode at 0 degrees C. Enantiomeric pur ity was greater than 99.8%ee for the (-)- and 90.5%ee for the (+)-enantiome r respectively. Optical rotation was determined to be [alpha](23)(D)= +/-13 degrees. Electrophysiological studies of 2PABH were carried out on alpha 4 beta 2, alpha 3 beta 4 and alpha 7 nAChR subtypes cloned from rat and reco nstituted in Xenopus oocytes. Both enantiomers could not significantly acti vate the heteromeric subtypes. The homomeric alpha 7 nAChR displays a high sensitivity only towards (-)-2PABH. The EC50 for (-)-2PABH and ACh were det ermined (32.5 +/- 9.5 mu M, 137.3 +/- 16.5 mu M) (-)-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.