Direct activation of GABAA receptors by loreclezole, an anticonvulsant drug with selectivity for the β-subunit

Abstract Loreclezole, an anticonvulsant and antiepileptic compound, potentiates γ-aminobutyric acid (GABA) type A receptor function, by interacting with a specific allosteric modulatory site on receptor β-subunits. A similar selectivity for GABA A receptor β-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 -[ 35 S]butylbicyclophosphorothionate ([ 35 S]TBPS) binding by up to 28% (at 5 μM) and 80% (at 10 μM), respectively. Higher concentrations (50–100 μM) of both compounds inhibited [ 35 S]TBPS binding with great efficacy, an effect mimicked by GABA. In contrast, the benzodiazepine diazepam increased [ 35 S]TBPS binding, but failed to inhibit this parameter, even at high concentrations. At concentrations of 50–100 μM, loreclezole induced inward Cl − currents in the absence of GABA, in Xenopus oocytes expressing human recombinant GABA A receptors, comprised of α 1 -, β 2 - and γ 2S -subunits. At 100 μM, the current evoked by loreclezole was 26% of that induced by 5 μM GABA. The current evoked by 100 μM propofol was 98% of that induced by 5 μM 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 β 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 β 1 -subunit may be responsible for its lack of hypnotic effect. © 1997 Published by Elsevier Science Ltd. All rights reserved.