Effects of pyridine ring substitutions on affinity, efficacy, and subtype selectivity of neuronal nicotinic receptor agonist epibatidine

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

Research output: Contribution to journalArticle

34 Scopus citations

Abstract

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 α2β2, α2β4, α3β2, α3β4, α4β2, or α4β4. Efficacy (relative to acetylcholine) and potency were measured electrophysiologically with oocytes expressing α3β4, α4β2, and α4β4. Hydroxy, dimethylamino, and trifluoromethanesulfonate analogs had affinities too low for accurate measurement. The bromo analog had affinities 4- to 55-fold greater at β2 than at β4-containing receptors, modestly greater efficacy at α4β4 than at α4β2, and 5- to 10-fold greater potency at a4β4 than at α3β4 or α4β2. The fluoro analog displayed affinities 52- to 875-fold greater at β2- than at β4-containing receptors, efficacy at α4β4 receptors 3-fold greater than at α4β2 and α3β4, and was equipotent at all receptors tested. The norchloro analog showed affinities 114- to 3500-fold greater at β2- than at β4-containing receptors, 2-fold greater efficacy at α4β2 and α4β4 than at α3β4, and 4- to 5-fold greater potency at α4β4 and α3β4 than at α4β2. The amino analog displayed affinities 10- to 115-fold greater at β2-than at β4-containing receptors, 3-fold greater efficacy at α3β4 than at α4β2, and 2- to 4-fold greater potency at α3β4 and α4β4 than at α4β2. Although these compounds displayed a variety of differences in affinity, efficacy, and potency, with one exception (binding affinity and functional potency at α4β4 receptors) there were no significant correlations among these properties.

Original languageEnglish (US)
Pages (from-to)1246-1252
Number of pages7
JournalJournal of Pharmacology and Experimental Therapeutics
Volume302
Issue number3
DOIs
StatePublished - Sep 2002

ASJC Scopus subject areas

  • Molecular Medicine
  • Pharmacology

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