Allyl m-Trifluoromethyldiazirine Mephobarbital: An Unusually Potent Enantioselective and Photoreactive Barbiturate General Anesthetic
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- 作者：Pavel Y. Savechenkov ; Xi Zhang ; David C. Chiara ; Deirdre S. Stewart ; Rile Ge ; Xiaojuan Zhou ; Douglas E. Raines ; Jonathan B. Cohen ; Stuart A. Forman ; Keith W. Miller ; Karol S. Bruzik
- 刊名：Journal of Medicinal Chemistry
- 出版年：2012
- 出版时间：July 26, 2012
- 年：2012
- 卷：55
- 期：14
- 页码：6554-6565
- 全文大小：509K
- 年卷期：v.55,no.14(July 26, 2012)
- ISSN：1520-4804
文摘
We synthesized 5-allyl-1-methyl-5-(m-trifluoromethyl-diazirynylphenyl)barbituric acid (<b>14b>), a trifluoromethyldiazirine-containing derivative of general anesthetic mephobarbital, separated the racemic mixture into enantiomers by chiral chromatography, and determined the configuration of the (+)-enantiomer as S by X-ray crystallography. Additionally, we obtained the 3H-labeled ligand with high specific radioactivity. R-(鈭?-<b>14b> is an order of magnitude more potent than the most potent clinically used barbiturate, thiopental, and its general anesthetic ECb>50 b> approaches those for propofol and etomidate, whereas S-(+)-<b>14b> is 10-fold less potent. Furthermore, at concentrations close to its anesthetic potency, R-(鈭?-<b>14b> both potentiated GABA-induced currents and increased the affinity for the agonist muscimol in human 伪1尾2/3纬2L GABAb>A b> receptors. Finally, R-(鈭?-<b>14b> was found to be an exceptionally efficient photolabeling reagent, incorporating into both 伪1 and 尾3 subunits of human 伪1尾3 GABAb>A b> receptors. These results indicate R-(鈭?-<b>14b> is a functional general anesthetic that is well-suited for identifying barbiturate binding sites on Cys-loop receptors.