title: Synthesis of trifluoromethylaryl diazirine and benzophenone derivatives of etomidate that are potent general anesthetics and effective photolabels for probing sites on ligand-gated ion channels.
abstract: To locate the binding sites of general anesthetics on ligand-gated ion channels, two derivatives of the intravenous general anesthetic etomidate (2-ethyl 1-(phenylethyl)-1H-imidazole-5-carboxylate), in which the 2-ethyl group has been replaced by photoactivable groups based on either aryl diazirine or benzophenone chemistry, have been synthesized and characterized pharmacologically. TDBzl-etomidate (4-[3-(trifluoromethyl)-3H-diazirin-3-yl]benzyl 1-(1-phenylethyl)-1H-imidazole-5-carboxylate) and BzBzl-etomidate (4-benzoylbenzyl-1-(1-phenylethyl)-1H-imidazole-5-carboxylate are both potent general anesthetics with half-effective anesthetic concentrations of 700 and 220 nM, respectively. Both agents resembled etomidate in enhancing currents elicited by low concentrations of GABA on heterologously expressed GABAA receptors and in shifting the GABA concentration-response curve to lower concentrations. They also allosterically enhanced the binding of flunitrazepam to mammalian brain GABAA receptors. Both agents were also effective and selective photolabels, photoincorporating into some, but not all, subunits of the Torpedo nicotinic acetylcholine receptor to a degree that was allosterically regulated by an agonist or a noncompetitive inhibitor. Thus, they have the necessary pharmacological and photochemical properties to be useful in identifying the site of etomidate-induced anesthesia.
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: Selvanayagam
authors.initials: S
authors.lastname: Nirthanan
authors.forename: Dirk
authors.initials: D
authors.lastname: Ruesch
authors.forename: Ken
authors.initials: K
authors.lastname: Solt
authors.forename: Qi
authors.initials: Q
authors.lastname: Cheng
authors.forename: Guo-Dong
authors.initials: GD
authors.lastname: Li
authors.forename: Enrique
authors.initials: E
authors.lastname: Arevalo
authors.forename: Richard W
authors.initials: RW
authors.lastname: Olsen
authors.forename: Douglas E
authors.initials: DE
authors.lastname: Raines
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* / Q000494:pharmacology; D000818:Animals; D001577:Benzophenones / Q000138:chemical synthesis* / Q000494:pharmacology; D001921:Brain / Q000378:metabolism; D002417:Cattle; D003978:Diazomethane / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000494:pharmacology; D005045:Etomidate / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000494:pharmacology; D005260:Female; D058785:GABA-A Receptor Agonists; D006801:Humans; D066298:In Vitro Techniques; D015640:Ion Channel Gating; D007473:Ion Channels / Q000187:drug effects*; D007814:Larva; D008024:Ligands; D009865:Oocytes / Q000187:drug effects / Q000502:physiology; D019920:Photoaffinity Labels / Q000138:chemical synthesis* / Q000494:pharmacology; D021122:Protein Subunits / Q000819:agonists / Q000502:physiology; D011963:Receptors, GABA-A / Q000502:physiology; D011978:Receptors, Nicotinic / Q000378:metabolism; D012018:Reflex / Q000187:drug effects; D014101:Torpedo; D014982:Xenopus laevis; D005680:gamma-Aminobutyric Acid / Q000494:pharmacology
chemical_list: C513361:4-(3-(trifluoromethyl)-3H-diazirin-3-yl)benzyl 1-(1-phenylethyl)-1H-imidazole-5-carboxylate; C513362:4-benzoylbenzyl 1-(1-phenylethyl)-1H-imidazole-5-carboxylate; D018681:Anesthetics, General; D001577:Benzophenones; D058785:GABA-A Receptor Agonists; D007473:Ion Channels; D008024:Ligands; D019920:Photoaffinity Labels; D021122:Protein Subunits; D011963:Receptors, GABA-A; D011978:Receptors, Nicotinic; D005680:gamma-Aminobutyric Acid; D003978:Diazomethane; D005045:Etomidate