A behavioural and neurochemical study in rats of the pharmacology of loreclezole, a novel allosteric modulator of the GABA(A) receptor

Loreclezole is an anticonvulsant and anxiolytic compound which has been reported to potentiate GABA via a novel allosteric site on the beta-subunit of the receptor. We have now studied in rats both the in vivo and in vitro pharmacology of the compound. The dose of loreclezole required to increase by 50% the dose of intravenous pentylenetetrazol eliciting a seizure was comparable to that of barbiturates and chlormethiazole (in mg/kg): diazepam, 1.3; pentobarbitone, 16; chlormethiazole, 22; loreclezole, 25; pentobarbitone, 36. Loreclezole dose-dependently decreased locomotion (dose to decrease locomotion by 50% (in mg/kg): chlormethiazole, 9; pentobarbitone, 16; loreclezole, 25). Loreclezole, chlormethiazole and pentobarbitone all failed to displace [H-3]muscimol and [H-3]flunitrazepam binding from a rat cortical membrane preparation. All three compounds fully displaced [S-35]TBPS binding (IC50 values: loreclezole, 4.34 +/- 0.68 mu M; pentobarbitone, 37.39 +/- 3.24 mu M; chlormethiazole, 82.10 +/- 8.52 mu M). Addition of bicuculline (10 mu M) produced a major rightward shift in the loreclezole and pentobarbitone displacement curves, increasing IC50 values for [S-35]TBPS binding by 25 times (loreclezole), 6 times (pentobarbitone) and 2.7 times (chlormethiazole), suggesting a greater involvement of GABA in the interaction of loreclezole with the chloride channel than in the case of chlormethiazole. Anticonvulsant activity of the compounds did not appear to relate to [S-35]TBPS binding activity. Other binding data suggested that although the evidence of others indicates that loreclezole interacts with a specific allosteric site on the beta-subunit, it nevertheless also alters the binding characteristics of other modulatory sites. Copyright (C) 1996 Elsevier Science Ltd