The mechanism of action of zopiclone

Summary The mechanism of action of the cyclopyrrolone hypnotic drug zopiclone involves allosteric modulation of the GABA A receptor. Zopiclone displaces the binding of [ 3 H]-flunitrazepam with an affinity of 28 nM, and enhances the binding of the channel blocker [ 35 S]-TBPS. The binding of zopiclone, unlike that of hypnotic benzodiazepines, is not facilitated by GABA. Zopiclone does not distinguish between GABAA receptors containing different α-subunits (BZ 1 and BZ 2 phenotype). Studies with protein-modifying agents ( eg diethylpyrocarbonate) and photoaffinity labelling suggest that cyclopyrrolones bind to a domain on the GABAA receptor different from the benzodiazepine binding domain. The consequence of this interaction with the GABA A receptor is to potentiate responses to 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 GABA A receptor that are observed with hypnotic benzodiazepines.