The effects of loreclezole on the function of the gamma-aminobutyric acid type A. (GABA(A)) receptor complex in rat cerebral cortical membrane preparations were compared with those of propofol and diazepam. Loreclezole and propofol modulated [H-3]muscimol binding and t-[S-35]butylbicyclophosphorothionate ([S-35]TBPS) binding to washed and unwashed membranes with potencies and efficacies greater than those of diazepam. Loreclezole and propofol enhanced [H-3]flunitrazepam binding to washed membranes with efficacies lower than those of GABA and muscimol. Both loreclezole and propofol showed biphasic effects on [S-35]TBPS binding to washed membranes: at low concentrations (5 to 10 mu M), both drugs, with different efficacies, enhanced [S-35]TBPS binding whereas, at higher concentrations (30 to 100 mu M), they inhibited this biochemical parameter. In contrast, diazepam enhanced [S-35]TBPS binding to washed membranes at all concentrations tested. The combination of loreclezole with GABA, at a concentration (0.3 mu M) that only slightly increased [S-35]TBPS binding to washed membranes, reversed the increase in binding elicited by loreclezole (5 to 10 mu M) and significantly potentiated the inhibitory effect exerted by higher concentrations (30 to 100 mu M) of this drug. Similar effects were observed with the combination of GABA and propofol. However, GABA had no effect on the enhancement of [S-35]TBPS binding induced by diazepam. The ability of GABA to reverse and potentiate the effects of loreclezole and propofol on [S-35]TBPS binding to washed membranes was shared by pentobarbital (200 mu M) and alphaxalone (3 mu M). These anesthetics showed greater efficacies in combination with propofol than with loreclezole. These results suggest that, unlike diazepam, loreclezole and propofol may activate the receptor-associated Cl- channel in the absence of GABA. Furthermore, the difference in the pharmacological profiles of loreclezole and propofol may result from their different effectiveness in activating the receptor Cl- channel directly.
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