The effect of cyclopyrrolones on GABA_A receptor function is different from that of benzodiazepines

Abstract

The effects of the cyclopyrrolones zopiclone and suriclone on the function of the central γ-aminobutyric acid type A (GABA_AA) receptor complex in mouse brain were evaluated both in vitro and in vivo. Added in vitro to mouse cerebral cortical membranes, these compounds potently inhibited [³H]flumazenil binding with IC₅₀ (50% inhibitory concentration) values of 35.8 nM (zopiclone) and 1.1 nM (suriclone). Similar results were obtained with cerebellar membranes, indicating that these drugs do not discriminate between putative type I and type II benzodiazepine receptors. The interaction of cyclopyrrolones with recognition sites present at the level of the GABA receptor complex appears to be competitive, because zopiclone decreased the affinity of the receptors for [³H]flumazenil without affecting the maximal number of binding sites. Moreover, zopiclone and suriclone did not affect the rate of dissociation of [³H]flumazenil from benzodiazepine receptors. The in vitro efficacy of zopiclone appeared different from that of suriclone and the benzodiazepines diazepam and flunitrazepam. Thus, zopiclone failed to affect muscimol-stimulated ³⁶Cl⁻ uptake and only slightly inhibited t-[³⁵S]butylbicyclophosphorothionate ([³⁵S]TBPS) binding. In contrast, like diazepam and flunitrazepam, suriclone increased muscimol-stimulated ³⁶Cl⁻ uptake and markedly inhibited [³⁵S]TBPS binding. On the other hand, suriclone, like zopiclone, did not modify [³H]muscimol binding to mouse cerebral cortical membranes. Moreover, zopiclone antagonized the reduction in [³⁵S]TBPS binding elicited by the benzodiazepine receptor full agonist diazepam. Consistent with its low efficacy in vitro, oral administration of zopiclone (2.5 to 100 mg/kg, p.o.) in mice failed to modify [³⁵S]TBPS binding subsequently measured in cerebral cortical membranes “ex vivo”. In contrast, suriclone (10 to 20 mg/kg, p.o.), like diazepam, decreased [³⁵S]TBPS binding measured ex vivo. Moreover, both zopiclone (50 to 100 mg/kg, p.o.) and suriclone (1 to 10 mg/kg, p.o.) abolished the increase in [³⁵S]TBPS binding induced by isoniazid (200 mg/kg, s.c.). These results suggest that suriclone may enhance GABAergic transmission with an efficacy similar to that of diazepam. In contrast, the low efficacy of zopiclone both in vitro and in vivo suggests that this drug may act as a partial agonist at benzodiazepine receptors.