Vol. 284, Issue 3, 886-894, March 1998

The Heterocyclic Substituted Pyridine Derivative (±)-2-(-3-pyridinyl)-1-Azabicyclo[2.2.2]octane (RJR-2429): A Selective Ligand at Nicotinic Acetylcholine Receptors

M. Bencherif, J. D. Schmitt, B. S. Bhatti, P. Crooks, W. S. Caldwell, M. E. Lovette, K. Fowler, L. Reeves and P. M. Lippiello

Pharmacology Division (M.B., W.S.C., M.E.L., K.F., L.R., P.M.L.), R.J. Reynolds Research & Development, Winston-Salem, North Carolina, School of Biochemistry and Biology (J.D.S.), University of Bath, Cleverton Down, Bath, United Kingdom, College of Pharmacy (B.S.B., P.C.), University of Kentucky, Lexington, Kentucky

The present report describes in vitro studies demonstrating that the heterocyclic substituted pyridine compound (±)-2-(3-pyridinyl)-1-azabicyclo[2.2.2]octane (RJR-2429) is extremely potent in activating human muscle nicotine ACh receptor (nAChR) (EC₅₀ = 59 ± 17 nM; E_max = 110 ± 09% vs. nicotine). RJR-2429 is markedly less potent in activating 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 putative 34-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 agonist-induced ileum contraction indicate that RJR-2429 is equipotent with nicotine, having an EC₃₀ of approximately 2 µM. RJR-2429 binds with high affinity to ₄₂ receptor subtype (K_i = 1.0 ± 0.3 nM), and chronic exposure results in significant up-regulation of the high-affinity [³H]nicotine binding sites. In addition, RJR-2429 does not activate nAChRs present in rat thalamic preparations but is a potent inhibitor of this receptor subtype. It antagonizes nicotine-stimulated ion flux in thalamic synaptosomes with an IC₅₀ of 154 ± 37 nM. It also is a potent partial agonist at nAChRs mediating dopamine release from rat synaptosomal preparations (EC₅₀ = 2 ± 1 nM; E_max = 40%; epibatidine and nicotine have EC₅₀ values of 0.4 and 100 nM, respectively). A model for the structure-activity profile of RJR-2429, nicotine and epibatidine was derived by molecular forcefield and quantum mechanics calculations and may provide important clues for the development of ligands selective for nAChR subtypes as probes in the life sciences or as potential therapeutic tools.