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2-(3-Methyl-3 H -diaziren-3-yl)ethyl 1-(1-phenylethyl)-1 H -imidazole-5-carboxylate: A Derivative of the Stereoselective General Anesthetic Etomidate for Photolabeling Ligand-Gated Ion Channels

2003; American Chemical Society; Volume: 46; Issue: 7 Linguagem: Inglês

10.1021/jm020465v

1520-4804

S. Shaukat Husain, Michael R. Ziebell, Dirk Ruesch, Filbert Hong, Enrique Arevalo, Jonathan A. Kosterlitz, Richard W. Olsen, Stuart A. Forman, Jonathan B. Cohen, Keith W. Miller,

Chemical Synthesis and Analysis

To locate general anesthetic binding sites on ligand-gated ion channels, a diazirine derivative of the potent intravenous anesthetic, R-(+)-etomidate (2-ethyl 1-(1-phenylethyl)-1H-imidazole-5-carboxylate), has been synthesized and characterized. R-(+)-Azietomidate [2-(3-methyl-3H-diaziren-3-yl)ethyl 1-(1-phenylethyl)-1H-imidazole-5-carboxylate] anesthetizes tadpoles with an EC50 of 2.2 μM, identical to that of R-(+)-etomidate. At this concentration both agents equally enhanced GABA-induced currents and decreased binding of the caged-convulsant [35S]TBPS to GABAA receptors. In all of the above actions R-(+)-azietomidate is about an order of magnitude more potent than S-(−)-azietomidate, an enantioselectivity comparable to etomidate's. R-(+)-Azietomidate also inhibits acetylcholine-induced currents in nicotinic acetylcholine receptors, with about twice the potency of the parent compound. [3H]Azietomidate photoincorporated into Torpedo nicotinic acetylcholine receptor-rich membranes. Desensitization decreased photoincorporation into the δ-subunit and increased that into the α-subunit. The latter increase was confined to a proteolytic fragment containing the first three transmembrane segments. Thus, R-(+)-azietomidate is a potent stereoselective general anesthetic and an effective photolabel.