On the inhibition of muscle membrane chloride conductance by aromatic carboxylic acids.

Abstract

Aromatic carboxylic acids (25), analogs of benzoic acid, were tested in the rat diaphragm preparation for effects on Cl- conductance (GCl). Of the 25, 19 reduced membrane GCl with little effect on other membrane parameters, although their apparent Ki varied widely. This inhibition was reversible if exposure times were not prolonged. The most effective analog studied was anthracene-9-COOH (9-AC; Ki = 1.1 .times. 10-5 M). Active analogs produced concentration-dependent inhibition of a type consistent with interaction at a single site or group of sites having similar binding affinities, although a correlation was also shown between lipophilicity and Ki. Structure-activity analysis indicated that hydrophobic ring substitution usually increased inhibitory activity while para polar substitutions reduced effectiveness. These compounds did not inhibit GCl by altering membrane surface charge and the inhibition produced was not voltage dependent. Qualitative characteristics of the I-V [current-voltage] relationship for Cl- current were not altered. Conductance to all anions was not uniformly altered by these acids as was expected from steric occlusion of a common channel. Concentrations of 9-AC reducing GCl by > 90% resulted in slight augmentation of GI. The complete conductance sequence obtained at high levels of 9-AC was the reverse of that obtained under control conditions. Permeability sequences underwent progressive changes with increasing 9-AC concentration and ultimately inverted at high levels of the analog. Aromatic carboxylic acids may inhibit GCl by binding to a specific intramembrane site and altering the selectivity sequence of the membrane anion channel.