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

J Med Chem. 2012 Jul 26;55(14):6554-65. doi: 10.1021/jm300631e. Epub 2012 Jul 17.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Anesthetics, General / chemistry*
  • Anesthetics, General / metabolism
  • Anesthetics, General / pharmacology*
  • Azirines / chemistry*
  • Humans
  • Light*
  • Mephobarbital / chemistry*
  • Mephobarbital / metabolism
  • Mephobarbital / pharmacology*
  • Receptors, GABA-A / metabolism
  • Solubility
  • Stereoisomerism
  • Substrate Specificity


  • Anesthetics, General
  • Azirines
  • Receptors, GABA-A
  • Mephobarbital