Vol. 302, Issue 3, 1246-1252, September 2002

Effects of Pyridine Ring Substitutions on Affinity, Efficacy, and Subtype Selectivity of Neuronal Nicotinic Receptor Agonist Epibatidine

Melva Avalos, Michael J. Parker¹ , Floyd N. Maddox, F. Ivy Carroll and Charles W. Luetje

Department of Molecular and Cellular Pharmacology, University of Miami School of Medicine, Miami, Florida (M.A., M.J.P., F.N.M, C.W.L.); and Chemistry and Life Sciences, Research Triangle Institute, Research Triangle Park, North Carolina (F.I.C.)

2'-Pyridine ring substituted analogs of epibatidine were assessed for equilibrium binding affinity, functional potency, and efficacy at rat neuronal nicotinic receptors expressed in Xenopus oocytes. Binding affinities were determined in membrane homogenates from oocytes expressing 22, 24, 32, 34, 42, or 44. Efficacy (relative to acetylcholine) and potency were measured electrophysiologically with oocytes expressing 34, 42, and 44. Hydroxy, dimethylamino, and trifluoromethanesulfonate analogs had affinities too low for accurate measurement. The bromo analog had affinities 4- to 55-fold greater at 2 than at 4-containing receptors, modestly greater efficacy at 44 than at 42, and 5- to 10-fold greater potency at a44 than at 34 or 42. The fluoro analog displayed affinities 52- to 875-fold greater at 2- than at 4-containing receptors, efficacy at 44 receptors 3-fold greater than at 42 and 34, and was equipotent at all receptors tested. The norchloro analog showed affinities 114- to 3500-fold greater at 2- than at 4-containing receptors, 2-fold greater efficacy at 42 and 44 than at 34, and 4- to 5-fold greater potency at 44 and 34 than at 42. The amino analog displayed affinities 10- to 115-fold greater at 2- than at 4-containing receptors, 3-fold greater efficacy at 34 than at 42, and 2- to 4-fold greater potency at 34 and 44 than at 42. Although these compounds displayed a variety of differences in affinity, efficacy, and potency, with one exception (binding affinity and functional potency at 44 receptors) there were no significant correlations among these properties.