Zopiclone

Zopiclone is a cyclopyrrolone hypnotic: one of the nonbenzodiazepine 'Z-drugs' used for short-term insomnia. It is a positive allosteric modulator of the GABA-A receptor: it binds at (or near) the benzodiazepine site at the interface between the α and γ subunits and increases the receptor's response to GABA, enhancing inhibitory chloride currents to produce sedation and sleep. It is sold as a racemate, a 1:1 mixture of the (R)- and (S)-enantiomers, under names such as Imovane and Zimovane, at 3.75–7.5 mg. Only the (S)-enantiomer is pharmacologically active. That single enantiomer is marketed on its own as eszopiclone (Lunesta in the US, Lunivia in Germany) at correspondingly lower doses of 1–3 mg. This page covers both the racemate and the enantiopure form. Cyclopyrrolones occupy the benzodiazepine site but are not benzodiazepines: their binding is not facilitated by GABA and depends on different receptor loops, and unlike zolpidem they do not strongly prefer α1-containing receptors. The two forms differ mainly in how their pharmacology has been measured. For the racemate, radioligand studies show high benzodiazepine-site affinity: Ki ≈ 24–36 nM across cortex, cerebellum and hippocampus. For the active (S)-enantiomer (eszopiclone), displacement assays on recombinant human receptors give Ki ≈ 50 nM (α1), 114 nM (α2), 162 nM (α3) and 102 nM (α4), with essentially no binding at α5 or α6 (> 15 µM): a comparatively non-selective α1–α4 profile. Both forms 'prime' α1β2γ2 receptors for a longer duration of channel activity. The clinical profile is dominated by sedation rather than the pronounced anxiolytic, muscle-relaxant or anticonvulsant effects more typical of benzodiazepines. Pharmacokinetics are broadly similar for the two forms. The racemate is well absorbed (oral bioavailability ≈75–80%), peaks at 1–2 h, is about 52–59% protein-bound and has an elimination half-life of ~5 hours (3.5–6.5 h), rising to 7–9 h in older people. It is metabolised in the liver by CYP3A4 and CYP2E1 through oxidation and demethylation. The main metabolites are N-desmethylzopiclone (pharmacologically active, mainly anxiolytic) and zopiclone-N-oxide (inactive), with about 80% excreted renally (largely as metabolites). Eszopiclone behaves similarly, with a half-life of ~6 h (~9 h in the elderly) and less than 10% excreted unchanged, because only the active enantiomer is administered its doses are about half those of the racemate, and the FDA lowered its recommended starting dose from 2 mg to 1 mg in 2014 because of next-morning impairment. A distinctive and very common side effect of both forms is dysgeusia, an unpleasant bitter or metallic taste, which, together with headache and dry mouth, is among the most frequently reported complaints and a common reason for stopping the drug.