期刊
JOURNAL OF MEDICINAL CHEMISTRY
卷 55, 期 14, 页码 6554-6565出版社
AMER CHEMICAL SOC
DOI: 10.1021/jm300631e
关键词
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资金
- National Institute for General Medicine [GM 58448]
- U.S. Department of Energy, Office of Science, Office of Basic Energy Sciences [DE-AC02-06CH11357]
- Michigan Economic Development Corporation
- Michigan Technology Tri-Corridor [085P1000817]
We synthesized 5-allyl-1-methyl-5-(m-trifluoromethyl-diazirynylphenyl)barbituric acid (14), 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 H-3-labeled ligand with high specific radioactivity. R-(-)-14 is an order of magnitude more potent than the most potent clinically used barbiturate, thiopental, and its general anesthetic EC50 approaches those for propofol and etomidate, whereas S-(+)-14 is 10-fold less potent. Furthermore, at concentrations close to its anesthetic potency, R-(-)-14 both potentiated GABA-induced currents and increased the affinity for the agonist muscimol in human alpha 1 beta 2/3 gamma 2L GABA(A) receptors. Finally, R-()-14 was found to be an exceptionally efficient photolabeling reagent, incorporating into both alpha 1 and beta 3 subunits of human alpha 1 beta 3 GABA(A) receptors. These results indicate R-(-)-14 is a functional general anesthetic that is well-suited for identifying barbiturate binding sites on Cys-loop receptors.
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