Opposite effects of enantiomers of clofibric acid derivative on rat skeletal muscle chloride conductance: antagonism studies and theoretical modeling of two different receptor site interactions

The R-(+) enantiomer of 2-(p-chlorophenoxy) propionic acid (CPP) produces a biphasic effect on chloride channel conductance (GCl) of rat skeletal muscle, increasing GCl at low concentrations and decreasing it at concentrations greater than 10-mu-M; on the other hand, the S-(-) isomer mostly blocks GCl in a concentration-dependent manner. To explain the peculiar behavior of these compounds, a theoretical model based on the presence of two opposing receptor populations controlling chloride channel conductance has been used to fit the experimental data of the concentration-response curves of both S-(-) and R-(+) CPP. An analysis performed by means of the algebraic summation of two logistic terms suggests a reasonable merit of the proposed model and explains the resultant effect of each optical form as follows: S-(-) acts as a full agonist on an inhibitory sites, whereas R-(+) acts as a full agonist at both the inhibitory and excitatory sites. Antagonism studies appear to be consistent with the proposed model. Dose-response curves in which the block of GCl by the S-(-) isomer was evaluated in the presence of the R-(+) isomer (3-10-mu-M) clearly showed an antagonistic interaction between the two enantiomers, with an increase in the S-(-) concentration for half-maximal block. The antagonism was overcome by high concentrations of S-(-), and this might be consistent with the hypothesis that the block of GCl is modulated by an inhibitory site at which the two enantiomers compete.