Pharmacological studies on a locust neuromuscular preparation.

Abstract

ABSTRACT The structure-activity relationships of agonists of the locust excitatory neuromuscular synapse have been reinvestigated, paying particular attention to the purity of compounds, and to the characteristics and repeatability of the muscle response. The concentrations of compounds required to stimulate contractions of the retractor unguis muscle equal in force to the neurally evoked contractions provided a measure of the relative potencies. Seven amino acids were capable of stimulating twitch contractions, glutamic acid being the most active, the others being analogues or derivatives of glutamic or aspartic acid. Aspartic acid itself had no excitatory activity. Excitatory activity requires possession of two acidic groups, separated by two or three carbon atoms, and an amino group α to a carboxyl. An L-configuration appears essential. The ω-acidic group may be a carboxyl, sulphinyl or sulphonyl group. Substitution of any of the functional groups generally causes total loss of excitatory activity, but an exception is found in kainic acid in which the nitrogen atom forms part of a ring. The investigation of a wide variety of compounds revealed neuromuscular blocking activity among isoxazoles, hydroxylamines, indolealkyl-amines, β-carbolines, phenazines and phenothiazines. No specific antagonist of the locust glutamate receptor was found, but synaptic blocking agents of moderately high activity are reported.