Allyl m-trifluoromethyldiazirine mephobarbital: an unusually potent enantioselective and photoreactive barbiturate general anesthetic.

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

Journal of medicinal chemistry 2012 Jul 26

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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 (3)H-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 EC(50) 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 α1β2/3γ2L GABA(A) receptors. Finally, R-(-)-14 was found to be an exceptionally efficient photolabeling reagent, incorporating into both α1 and β3 subunits of human α1β3 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.

Citation

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. Allyl m-trifluoromethyldiazirine mephobarbital: an unusually potent enantioselective and photoreactive barbiturate general anesthetic. Journal of medicinal chemistry. 2012 Jul 26;55(14):6554-65