Molecular Pharmacology, Vol 18, 20-27, Copyright © 1980 by the American Society for Pharmacology and Experimental Therapeutics

Structural Requirements for Agonist and Noncompetitive Blocking Action of Acylcholine Derivatives on Electrophorus electricus Electroplaque

¹ Département de Chimie Organique, ERA 613 (CNRS), UER des Sciences Pharmaceutiques et Biologiques, 4 avenue de l’Observatoire, 75270 Paris Cedex 06, France
² Neurobiologie Moléculaire et Laboratoire Interactions Moléculaires et Cellulaires associé au CNRS, Institut Pasteur, 25 rue du Docteur Roux, 75015 Paris, France

Several series of acyl analogs of acetylcholine (including fluorescent ones) were synthesized and their pharmacological properties investigated on Electrophorus electricus electroplaque. Their action as agonist, noncompetitive blocker, or mixed agonist-noncompetitive blocker depends both on the nature of the N-terminal substituent and on the length of the alkyl chain. The C₁, C₂, and C₃ members of the dansylamidoacyicholine (C_nDAChol) and naphthylsulfonamidoacylcholine (C_nAChol) series behave as noncompetitive blocking agents, while the C₄, C₅, and C₇ analogs exhibit a significant agonist character in addition to their noncompetitive effect. This difference might result from the folding of the ammonium group on top of the aromatic ring which would prevent access of the C₁ to C₃ members of the series to the agonist binding site. The C₁₀DAChol and NAChol are powerful noncompetitive blockers and, at variance with other members of the series, form micelles in aqueous solution. Replacement of the N-terminal aromatic ring by a polar alkyl group (as in methylsulfonamidoacylcholine) abolishes the noncompetitive blocking properties and yields a series of potent full agonists. The apparent affinity of the agonists thus obtained increases with the length of the polymethylene spacer. The partial agonistic character of some of the compounds synthesized is interpreted as resulting from their dual pharmacological action as agonists and noncompetitive blockers binding to two distinct classes of membrane sites.

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ACKNOWLEDGMENTS We thank Simone Mougeon for her skill and initiative in performing the experiments with Electrophorus electroplaque, Thierry Heidmann for stimulating discussions, and Annick Bouju for typing the manuscript.