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.