THE MECHANISM OF ACTION OF ZOPICLONE

The mechanism of action of the cyclopyrrolone hypnotic drug zopiclone involves allosteric modulation of the GABAA receptor. Zopiclone displa ces the binding of [H-3]-flunitrazepam with an affinity of 28 nM, and enhances the binding of the channel blocker [S-35]-TBPS. The binding o f zopiclone, unlike that of hypnotic benzodiazepines, is not facilitat ed by GABA. Zopiclone does not distinguish between GABA(A) receptors c ontaining different alpha-subunits (BZ(1) and BZ(2) phenotype). Studie s with protein-modifying agents (eg diethylpyrocarbonate) and photoaff inity labelling suggest that cyclopyrrolones bind to a domain on the G ABAA receptor different from the benzodiazepine binding domain. The co nsequence of this interaction with the GABA, as can be demonstrated by electrophysiological methods. Subchronic treatment of mice with high doses of zopiclone does not produce the changes in sensitivity of the GABAA receptor that are observed with hypnotic benzodiazepines.