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 microM; 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 microM) 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.
De Luca
A
A
Department of Pharmacobiology, University of Bari, Italy.
Tricarico
D
D
Wagner
R
R
Bryant
S H
SH
Tortorella
V
V
Conte Camerino
D
D
D008456:2-Methyl-4-chlorophenoxyacetic Acid / Q000031:analogs & derivatives / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000494:pharmacology; D000818:Animals; D001665:Binding Sites; D018118:Chloride Channels; D002712:Chlorides / Q000502:physiology*; D002995:Clofibric Acid / Q000031:analogs & derivatives*; D066298:In Vitro Techniques; D007700:Kinetics; D008297:Male; D008565:Membrane Proteins / Q000187:drug effects* / Q000378:metabolism; D008954:Models, Biological; D009132:Muscles / Q000187:drug effects* / Q000502:physiology / Q000648:ultrastructure; D051381:Rats; D011919:Rats, Inbred Strains; D013237:Stereoisomerism
D018118:Chloride Channels; D002712:Chlorides; D008565:Membrane Proteins; C048213:2-(4-chlorophenoxy)propionic acid; D002995:Clofibric Acid; D008456:2-Methyl-4-chlorophenoxyacetic Acid