p-Trifluoromethyldiazirinyl-etomidate: A Potent Photoreactive General Anesthetic Derivative of Etomidate That Is Selective for Ligand-Gated Cationic Ion Channels

We synthesized the R- and S-enantiomers of ethyl 1-(1-(4-(3-((trilluoromethyl)-3H-diazirin-3-yl)-phenyl)ethyl)-1H-imidazole-5-carboxylate (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) ((alpha 1)(2)beta 1 delta 1 gamma 1) and 5-HT3AR (serotonin type 3A receptor), causing significant inhibition at anesthetic concentrations. S- but not R-TFD-etomiclate enhanced currents elicited from inhibitory alpha 1 beta 2 gamma 2L 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. [H-3]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.