Separate site(s) of action of optical isomers of 1-methyl-5-phenyl-5-propylbarbituric acid with opposite pharmacological activities at the GABA receptor complex

Abstract

The behavioral profile of the optical isomers of 1-methyl-5-phenyl-5-propylbarbituric acid (MPPB) and their interaction with the convulsant binding site at the GABA receptor complex were investigated. R(−)-MPPB produced dose-related loss of righting reflex, whereas S(+)MPPB produced convulsions in a dose-dependent manner. Subconvulsive doses of S(+)MPPB were proconvulsant with a subeffective dose of picrotoxin. S(+)MPPB-induced seizures were blocked by R(−)MPPB and pentobarbital. In contrast, S(+)MPPB did not block the loss of righting reflex produced by R(−)MPPB or pentobarbital. S(+)MPPB inhibited the binding of [ 35S]t-butylbicyclophosphorothionate (TBPS), a ligand that binds to the picrotoxin site on the oligomeric GABA receptor complex, to rat brain membranes competitively, whereas R(−)MPPB inhibited it noncompetitively. Thus, the optical isomer of MPPB, which have opposite pharmacological effects, interact differently with the convulsant (TBPS) site at the GABA receptor complex. These results suggest that the convulsant S(+)MPPB and the depressant R(−)MPPB may produce their behavioral effects by acting via convulsant and anticonvulsant sites, respectively, at the GABA receptor complex.