Zopiclone enantiomers

Fernandez C, Alt P, Davrinche C, Adrien J, Thuillier A, Farinotti R, Gimenez F (2002) Stereoselective distribution and stereoconversion of zopiclone enantiomers in plasma and brain tissues in rats. J Pharm Pharmacol 54 335-340... 

Tang KW, Chen YY, Liu JJ. Resolution of zopiclone enantiomers by biphasic recognition chiral extraction. Sep. Purif. Technol. 2008 62(3) 681-686. 

Zopiclone is widely used as a sedative-hypnotic. It is metabolized to an inactive N-desmethylated derivative and an active N-oxide compound, both of which contain chiral centres. S-Zopiclone has a 50-fold higher affinity for the benzodiazepine receptor site than the R-enantiomer. This could be therapeutically important, particularly if the formation and the urinary excretion of the active metabolite benefits the S-isomer, which appears to be the case. As the half-life of the R-enantiomer is longer than that of the S-form, it would seem advantageous to use the R-isomer in order to avoid the possibility of daytime sedation and hangover effects which commonly occur with long-acting benzodiazepine receptor agonists. 

Zopiclone is a chiral cyclopyrrolone with hypnotic properties, possessing a pharmaceutical profile of high efficacy and low toxicity, similar to that of benzodiazepines. Zopiclone has been commercialized as a racemic mixture however, the (S)-enantiomer is more active and less toxic than the (R)-enantiomer [11]. Although enzymatic hydrolysis of esters or transesteriflcation processes of alcohols have been widely applied for enzymatic resolution or desymmetrization... 

Several drugs with novel chemical structures have been introduced more recently for use in sleep disorders. Zolpidem, an imidazopyridine, zaleplon, a pyrazolopyrimidine, and eszopiclone, a cyclopyrrolone (Figure 22-4), although structurally unrelated to benzodiazepines, share a similar mechanism of action, as described below. Eszopiclone is the (S) enantiomer of zopiclone, a hypnotic drug that has been available outside the United States since 1989. Ramelteon, a melatonin receptor agonist, is a new hypnotic drug (see Ramelteon). Buspirone is a slow-onset anxiolytic agent whose actions are quite different from those of conventional sedative-hypnotics (see Buspirone). 

An 86-year-old white woman taking nefazodone for depression started to take zopiclone for insomnia, but subsequently had morning drowsiness (37). The plasma concentration of zopiclone was measured 8 hours after administration on two occasions, during and after nefazodone therapy. After withdrawal of nefazodone, the plasma concentration of the -enantiomer of zopiclone fell from 107 to 17 ng/ml, while the plasma concentration of the i -enantiomer fell from 21 to 1.5 ng/ml. 

Long-term adaptations of zopiclone, a mixture of an active S enantiomer and an inactive R enantiomer, have not been well studied, but chronic studies of the active isomer eszopiclone suggest lack of notable tolerance or dependence developing over time... 

The active enantiomer of zopiclone, eszopiclone, has received an approvable leffer from fhe Unifed Sfafes Food and Drug Adminisfraflon... 

Advances in industrial chemical processes have allowed pharmaceutical manufacturers to take drugs that were originally marketed in racemic form and divide them into individual enantiomers, each of which may have unique properties. For some drugs, such as zopiclone, only one enantiomer (eszopiclone) is active the FDA has allowed such once-generic drugs to be patented and marketed under another name. In other cases, such as ibuprofen, both enantiomers produce the same effects. Steroid receptor sites also show stereoisomer specificity. 

Carlson JN, Haskew R, Maisonneuve IM, et al. Sedative and anxiolytic effects of zopiclone s enantiomers and metabolite. Eur J Pharmacol 2001 414 181-189. 

Fernandez, C. Maradeix, V. Gimenez, F. Thuillier, A. Farinotti, R. Pharmacokinetics of zopiclone and its enantiomers in Caucasian young healthy volunteers. Drug Metab. Dispos. 1993, 21, 1125-1128. 

It is worth nodng that more recendy the S (-l-)-enandomer of zopiclone, eszopiclone (Fig. 13.9) has been licensed. The S(-l-)-enantiomer is reported to have greater aaivity than the R(—)-enandomer with a 50-fold higher affinity for the GABA-A receptor and it is also suggested that it is superior in terms of the side effects profile. 

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