THE HETEROCYCLIC SUBSTITUTED PYRIDINE DERIVATIVE (+ -)-2-(-3-PYRIDINYL)-1-AZABICYCLO[2.2.2]OCTANE (RJR-2429) - A SELECTIVE LIGAND AT NICOTINIC ACETYLCHOLINE-RECEPTORS/

The present report describes in vitro studies demonstrating that the h eterocyclic substituted pyridine compound (+/-)-2-(3-pyridinyl)-1-azab icyclo[2.2.2]octane (RJR-2429) is extremely potent in activating human muscle nicotine ACh receptor (nAChR) (EC50 = 59 +/- 17 nM; E-max = 11 0 +/- 09% vs. nicotine). RJR-2429 is markedly less potent in activatin g nAChRs in the clonal cell line PC12, with EC50 = 1100 +/- 230 nM and E-max = 85 +/- 20% when compared with nicotine. The activation of a p utative alpha 3 beta 4-containing nAChR in PC12 by RJR-2429 reveals a potency intermediate between nicotine and epibatidine (EC50 of 20,000 nM for nicotine and 30 nM for epibatidine). Dose-response curves for a gonist-induced ileum contraction indicate that RJR-2429 is equipotent with nicotine, having an EC30 of approximately 2 mu M. RJR-2429 binds with high affinity to alpha(4) beta(2)receptor subtype (K-i = 1.0 +/- 0.3 nM), and chronic exposure results in significant up-regulation of the high-affinity [H-3]nicotine binding sites. In addition, RJR-2429 d oes not activate nAChRs present in rat thalamic preparations but is a potent inhibitor of this receptor subtype. It antagonizes nicotine-sti mulated ion flux in thalamic synaptosomes with an IC50 of 154 +/- 37 n M. It also is a potent partial agonist at nAChRs mediating dopamine re lease from rat synaptosomal preparations (EC50 = 2 +/- 1 nM; E-max = 4 0%; epibatidine and nicotine have EC50 values of 0.4 and 100 nM, respe ctively). A model for the structure-activity profile of RJR-2429, nico tine and epibatidine was derived by molecular forcefield and quantum m echanics calculations and may provide important clues for the developm ent of ligands selective for nAChR subtypes as probes in the life scie nces or as potential therapeutic tools.