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 interacting with a specific allosteric modulatory site on receptor beta-subunits. A similar selectivity for GABA(A) receptor beta-subunits is apparent for the direct activation of receptor-operated Cl- channels, by the general anesthetics propofol and pentobarbital. The ability of loreclezole to activate GABA(A) receptors directly has now been compared, biochemically 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]TBPS) binding by up to 28% (at 5 mu M) and 80% (at 10 mu M), respectively. Higher concentrations (50-100 mu M) of both compounds inhibited [S-35]TBPS binding with great efficacy, an effect mimicked by GABA. In contrast, the benzodiazepine diazepam increased [S-35]TBPS binding, but failed to inhibit this parameter, even at high concentrations. At concentrations 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)-subunits. At 100 mu M, the current evoked by loreclezole was 26% of that induced 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 flumazenil-sensitive manner and blocked by either bicuculline or picrotoxin. These data suggest that loreclezole shares, with propofol, an agonistic action at GABA(A) receptors containing the beta(2)-subunit and that the different efficacies of the two compounds in this regard, may underlie the difference in their pharmacological profiles. The failure of loreclezole to activate GABA(A) receptors containing the beta(1)-subunit may be responsible for its lack of hypnotic effect. (C) 1997 Published by Elsevier Science Ltd.