McMahon Lance R, Jerussi Thomas P, France Charles P
Department of Pharmacology, The University of Texas Health Science Center at San Antonio, 7703 Floyd Curl Drive, San Antonio, TX 78229-3900, USA.
Psychopharmacology (Berl). 2003 Jan;165(3):222-8. doi: 10.1007/s00213-002-1286-9. Epub 2002 Nov 14.
The behavioral effects of racemic zopiclone are similar to those of benzodiazepines that positively modulate GABA at the GABA(A) receptor complex; however, it is not clear how enantiomers or metabolites of zopiclone contribute to the benzodiazepine-like behavioral effects of racemic zopiclone.
Racemic zopiclone, its ( R)- and ( S)- enantiomers, and the ( S)-N-desmethyl metabolite, were evaluated for discriminative stimulus effects in untreated and diazepam treated rhesus monkeys.
One group of monkeys discriminated the benzodiazepine midazolam and another group, treated daily with the benzodiazepine diazepam (5.6 mg/kg, PO), discriminated the benzodiazepine antagonist flumazenil.
( RS)-Zopiclone (0.32-17.8 mg/kg) and ( S)-zopiclone (0.1-10 mg/kg) substituted with similar potencies for midazolam (>/=80% midazolam-appropriate responding). The midazolam-like discriminative stimulus effects of ( RS)-zopiclone were antagonized by flumazenil (p K(B)=7.52). ( R)-Zopiclone occasioned a maximum 45% midazolam-appropriate responding at a dose of 100 mg/kg; ( S)-desmethylzopiclone produced saline-appropriate responding up to a dose of 100 mg/kg. All four test compounds occasioned predominantly vehicle-appropriate responding in diazepam treated monkeys discriminating flumazenil. ( RS)-Zopiclone (10 mg/kg) attenuated the discriminative stimulus effects of flumazenil in diazepam treated monkeys.
These results clearly demonstrate that in rhesus monkeys the discriminative stimulus effects of zopiclone are stereoselective and qualitatively similar to those of midazolam. These results fail to show any benzodiazepine-like or benzodiazepine antagonist-like discriminative stimulus effects for ( S)- N-desmethylzopiclone, suggesting that any behavioral (e.g. anxiolytic) effects of this compound are not the result of actions at benzodiazepine receptors.
消旋佐匹克隆的行为效应与在GABA(A)受体复合物上正向调节GABA的苯二氮䓬类药物相似；然而，尚不清楚佐匹克隆的对映体或代谢物如何导致消旋佐匹克隆的苯二氮䓬样行为效应。
评估消旋佐匹克隆、其(R)-和(S)-对映体以及(S)-N-去甲基代谢物在未经治疗和地西泮治疗的恒河猴中的辨别刺激效应。
一组猴子辨别苯二氮䓬类药物咪达唑仑，另一组每天接受苯二氮䓬类药物地西泮(5.6mg/kg，口服)治疗，辨别苯二氮䓬类拮抗剂氟马西尼。
(RS)-佐匹克隆(0.32 - 17.8mg/kg)和(S)-佐匹克隆(0.1 - 10mg/kg)以相似的效力替代咪达唑仑(≥80%的咪达唑仑适当反应)。(RS)-佐匹克隆的咪达唑仑样辨别刺激效应被氟马西尼拮抗(pK(B)=7.52)。(R)-佐匹克隆在剂量为100mg/kg时引起最大45%的咪达唑仑适当反应；(S)-去甲基佐匹克隆在剂量高达100mg/kg时产生盐水适当反应。在辨别氟马西尼的地西泮治疗的猴子中，所有四种受试化合物主要引起载体适当反应。(RS)-佐匹克隆(10mg/kg)减弱了地西泮治疗的猴子中氟马西尼的辨别刺激效应。
这些结果清楚地表明，在恒河猴中，佐匹克隆的辨别刺激效应具有立体选择性，并且在质量上与咪达唑仑相似。这些结果未能显示(S)-N-去甲基佐匹克隆有任何苯二氮䓬样或苯二氮䓬拮抗剂样辨别刺激效应，表明该化合物的任何行为(如抗焦虑)效应不是作用于苯二氮䓬受体的结果。
