Agonist recognition site of the peripheral acetylcholine receptor ion channel complex differentiates the enantiomers of nicotine

R Rozental, Y Aracava, GT Scoble, KL Swanson, S Wonnacott and EX Albuquerque

Department of Pharmacology and Experimental Therapeutics, University of Maryland, School of Medicine, Baltimore.

The multiple actions of nicotine enantiomers at the peripheral nicotinic acetylcholine receptor were evaluated using electrophysiological and biochemical techniques. The alpha-bungarotoxin binding site showed a 6-fold greater affinity for (-)-nicotine than for the (+)-isomer, and this stereoselectivity was reflected in differences in the ability of the alkaloids to activate physiological responses in the forms of single ion channel currents, endplate depolarizations and muscle contractures. (-)-Nicotine was also more potent to induce slow desensitization. In contrast, both (-)- and (+)-nicotine were equipotent as ion channel blockers. Ion channel blockade occurred at effective agonist concentrations for (+)-nicotine but above the effective concentration for (-)-nicotine. The rapid and reversible interaction of nicotine enantiomers with the ion channel occurred at concentrations which implicate a significant contribution of channel blockade to the inhibition of indirect muscle twitch. The agonistic and ion channel blocking effects of the nicotine enantiomers provide important clues regarding the mechanisms by which nicotine may affect central nervous system nicotinic receptors.

Volume 251, Issue 2, pp. 395-404, 11/01/1989
Copyright © 1989 by American Society for Pharmacology and Experimental Therapeutics