Allyl m-trifluoromethyldiazirine mephobarbital: an unusually potent enantioselective and photoreactive barbiturate general anesthetic.
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.
Department of Anesthesia, Critical Care and Pain Medicine, Massachusetts General Hospital, 32 Fruit Street, Boston, MA 02114, USA.
Pavel Y
PY
Savechenkov
Xi
X
Zhang
David C
DC
Chiara
Deirdre S
DS
Stewart
Rile
R
Ge
Xiaojuan
X
Zhou
Douglas E
DE
Raines
Jonathan B
JB
Cohen
Stuart A
SA
Forman
Keith W
KW
Miller
Karol S
KS
Bruzik
D018681:Anesthetics, General / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*; D001389:Azirines / Q000737:chemistry*; D006801:Humans; D008027:Light; D008618:Mephobarbital / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*; D011963:Receptors, GABA-A / Q000378:metabolism; D012995:Solubility; D013237:Stereoisomerism; D013379:Substrate Specificity
D018681:Anesthetics, General; D001389:Azirines; D011963:Receptors, GABA-A; D008618:Mephobarbital