title: 2-(3-Methyl-3H-diaziren-3-yl)ethyl 1-(1-phenylethyl)-1H-imidazole-5-carboxylate: a derivative of the stereoselective general anesthetic etomidate for photolabeling ligand-gated ion channels.
abstract: 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 EC(50) of 2.2 microM, identical to that of R-(+)-etomidate. At this concentration both agents equally enhanced GABA-induced currents and decreased binding of the caged-convulsant [(35)S]TBPS to GABA(A) 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. [(3)H]Azietomidate photoincorporated into Torpedo nicotinic acetylcholine receptor-rich membranes. Desensitization decreased photoincorporation into the delta-subunit and increased that into the alpha-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.
authors.affiliation: Department of Anesthesia and Critical Care, Massachusetts General Hospital, Boston, Massachusetts 02114, USA.
authors.forename: S Shaukat
authors.initials: SS
authors.lastname: Husain
authors.forename: Michael R
authors.initials: MR
authors.lastname: Ziebell
authors.forename: Dirk
authors.initials: D
authors.lastname: Ruesch
authors.forename: Filbert
authors.initials: F
authors.lastname: Hong
authors.forename: Enrique
authors.initials: E
authors.lastname: Arevalo
authors.forename: Jonathan A
authors.initials: JA
authors.lastname: Kosterlitz
authors.forename: Richard W
authors.initials: RW
authors.lastname: Olsen
authors.forename: Stuart A
authors.initials: SA
authors.lastname: Forman
authors.forename: Jonathan B
authors.initials: JB
authors.lastname: Cohen
authors.forename: Keith W
authors.initials: KW
authors.lastname: Miller
mesh_terms: D000494:Allosteric Regulation; D018681:Anesthetics, General / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D000818:Animals; D001665:Binding Sites; D005045:Etomidate / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D018755:GABA Agonists / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D007093:Imidazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D066298:In Vitro Techniques; D015640:Ion Channel Gating; D007814:Larva; D008024:Ligands; D051379:Mice; D009865:Oocytes / Q000187:drug effects / Q000502:physiology; D018408:Patch-Clamp Techniques; D019920:Photoaffinity Labels / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011963:Receptors, GABA-A / Q000187:drug effects / Q000502:physiology; D011978:Receptors, Nicotinic / Q000187:drug effects / Q000502:physiology; D012018:Reflex / Q000187:drug effects; D013237:Stereoisomerism; D014101:Torpedo; D014981:Xenopus; D005680:gamma-Aminobutyric Acid / Q000494:pharmacology
chemical_list: D018681:Anesthetics, General; D018755:GABA Agonists; D007093:Imidazoles; D008024:Ligands; D019920:Photoaffinity Labels; D011963:Receptors, GABA-A; D011978:Receptors, Nicotinic; C473483:azietomidate; D005680:gamma-Aminobutyric Acid; D005045:Etomidate