PREJUNCTIONAL EFFECT OF QUATERNARY DERIVATIVES OF L-HYOSCYAMINE AT THE RAT NEUROMUSCULAR-JUNCTION - A STRUCTURE-ACTIVITY RELATIONSHIP STUDY

1. The effects of phenthonium and related compounds on the spontaneous release of acetylcholine (ACh) were investigated with electrophysiolo gical and radiolabelled techniques to correlate the prejunctional effe ct with their cholinolytic activities and to determine the structure-a ctivity relationship. 2. Phenthonium and endophen are N-(4-phenyl)-phe nacyl derivatives of l-hyoscyamine in ''exo'' and ''endo'' conformatio n, respectively. Tropol is N-(4-phenyl) phenacyl tropan-3-ol whereas i pratropium is 8-isopropyl-noratropine. 3. Only phenthonium increased t he frequency of miniature endplate potentials and the resting efflux o f spontaneous [H-3]-ACh in rat diaphragm muscles. 4. The rank order of the antimuscarinic potency was: ipratropium > atropine > phenthonium = endaphen > tropol. The rank order of the antinicotinic activity was: phenthonium = endophen > tropol > atropine > ipratropium. 5. It is co ncluded that the prejunctional facilitatory effect of phenthonium is a ssociated with the N-phenyl-phenacyl group at ''exo'' conformation but the effect is unrelated to its cholinolytic properties.