Husain_2010_J.Med.Chem_53_6432

Reference

Title : p-Trifluoromethyldiazirinyl-etomidate: a potent photoreactive general anesthetic derivative of etomidate that is selective for ligand-gated cationic ion channels - Husain_2010_J.Med.Chem_53_6432
Author(s) : Husain SS , Stewart D , Desai R , Hamouda AK , Li SG , Kelly E , Dostalova Z , Zhou X , Cotten JF , Raines DE , Olsen RW , Cohen JB , Forman SA , Miller KW
Ref : Journal of Medicinal Chemistry , 53 :6432 , 2010
Abstract :

We synthesized the R- and S-enantiomers of ethyl 1-(1-(4-(3-((trifluoromethyl)-3H-diazirin-3-yl)phenyl)ethyl)-1H-imidazole-5-carbo xylate (trifluoromethyldiazirinyl-etomidate), or TFD-etomidate, a novel photoactivable derivative of the stereoselective general anesthetic etomidate (R-(2-ethyl 1-(phenylethyl)-1H-imidazole-5-carboxylate)). Anesthetic potency was similar to etomidate's, but stereoselectivity was reversed and attenuated. Relative to etomidate, TFD-etomidate was a more potent inhibitor of the excitatory receptors, nAChR (nicotinic acetylcholine receptor) ((alpha1)(2)beta1delta1gamma1) and 5-HT(3A)R (serotonin type 3A receptor), causing significant inhibition at anesthetic concentrations. S- but not R-TFD-etomidate enhanced currents elicited from inhibitory alpha1beta2gamma2L GABA(A)Rs by low concentrations of GABA, but with a lower efficacy than R-etomidate, and site-directed mutagenesis suggests they act at different sites. [(3)H]TFD-etomidate photolabeled the alpha-subunit of the nAChR in a manner allosterically regulated by agonists and noncompetitive inhibitors. TFD-etomidate's novel pharmacology is unlike that of etomidate derivatives with photoactivable groups in the ester position, which behave like etomidate, suggesting that it will further enhance our understanding of anesthetic mechanisms.

PubMedSearch : Husain_2010_J.Med.Chem_53_6432
PubMedID: 20704351

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Citations formats

Husain SS, Stewart D, Desai R, Hamouda AK, Li SG, Kelly E, Dostalova Z, Zhou X, Cotten JF, Raines DE, Olsen RW, Cohen JB, Forman SA, Miller KW (2010)
p-Trifluoromethyldiazirinyl-etomidate: a potent photoreactive general anesthetic derivative of etomidate that is selective for ligand-gated cationic ion channels
Journal of Medicinal Chemistry 53 :6432

Husain SS, Stewart D, Desai R, Hamouda AK, Li SG, Kelly E, Dostalova Z, Zhou X, Cotten JF, Raines DE, Olsen RW, Cohen JB, Forman SA, Miller KW (2010)
Journal of Medicinal Chemistry 53 :6432