DIRECT ACTIVATION OF GABA(A) RECEPTORS BY LORECLEZOLE, AN ANTICONVULSANT DRUG WITH SELECTIVITY FOR THE BETA-SUBUNIT

Loreclezole, an anticonvulsant and antiepileptic compound, potentiates gamma-aminobutyric acid (GABA) type A receptor function, by interacti ng with a specific allosteric modulatory site on receptor beta-subunit s. A similar selectivity for GABA(A) receptor beta-subunits is apparen t for the direct activation of receptor-operated Cl- channels, by the general anesthetics propofol and pentobarbital. The ability of lorecle zole to activate GABA(A) receptors directly has now been compared, bio chemically and electrophysiologically, with that of propofol. in well- washed rat cortical membranes (devoid of endogenous GABA), loreclezole and propofol increased t-[S-35]butylbicyclophosphorothionate ([S-35]T BPS) binding by up to 28% (at 5 mu M) and 80% (at 10 mu M), respective ly. Higher concentrations (50-100 mu M) of both compounds inhibited [S -35]TBPS binding with great efficacy, an effect mimicked by GABA. In c ontrast, the benzodiazepine diazepam increased [S-35]TBPS binding, but failed to inhibit this parameter, even at high concentrations. At con centrations of 50-100 mu M, loreclezole induced inward Cl- currents in the absence of GABA, in Xenopus oocytes expressing human recombinant GABA(A) receptors, comprised of alpha(1)-, beta(2)- and gamma(2S)-subu nits. At 100 mu M, the current evoked by loreclezole was 26% of that i nduced by 5 mu M GABA. The current evoked by 100 mu M propofol was 98% of that induced by 5 mu M GABA. Currents induced by loreclezole, like those evoked by propofol, were potentiated by diazepam in a flumazeni l-sensitive manner and blocked by either bicuculline or picrotoxin. Th ese data suggest that loreclezole shares, with propofol, an agonistic action at GABA(A) receptors containing the beta(2)-subunit and that th e different efficacies of the two compounds in this regard, may underl ie the difference in their pharmacological profiles. The failure of lo reclezole to activate GABA(A) receptors containing the beta(1)-subunit may be responsible for its lack of hypnotic effect. (C) 1997 Publishe d by Elsevier Science Ltd.