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J Med Chem
2010 Sep 09;5317:6432-44. doi: 10.1021/jm100498u.
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p-Trifluoromethyldiazirinyl-etomidate: a potent photoreactive general anesthetic derivative of etomidate that is selective for ligand-gated cationic ion channels.
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
.
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We synthesized the R- and S-enantiomers of ethyl 1-(1-(4-(3-((trifluoromethyl)-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) ((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.
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20704351
???displayArticle.pmcLink???PMC3117435 ???displayArticle.link???J Med Chem ???displayArticle.grants???[+]
Alifimoff,
Anaesthetic potencies of primary alkanols: implications for the molecular dimensions of the anaesthetic site.
1989, Pubmed
Alifimoff,
Anaesthetic potencies of primary alkanols: implications for the molecular dimensions of the anaesthetic site.
1989,
Pubmed
Bali,
Defining the propofol binding site location on the GABAA receptor.
2004,
Pubmed
,
Xenbase
Belelli,
The interaction of the general anesthetic etomidate with the gamma-aminobutyric acid type A receptor is influenced by a single amino acid.
1997,
Pubmed
,
Xenbase
Blanton,
Identification and characterization of membrane-associated polypeptides in Torpedo nicotinic acetylcholine receptor-rich membranes by hydrophobic photolabeling.
2001,
Pubmed
Bright,
Identification of anesthetic binding sites on human serum albumin using a novel etomidate photolabel.
2007,
Pubmed
Charlesworth,
Anaesthetic modulation of nicotinic ion channel kinetics in bovine chromaffin cells.
1995,
Pubmed
Desai,
Gamma-amino butyric acid type A receptor mutations at beta2N265 alter etomidate efficacy while preserving basal and agonist-dependent activity.
2009,
Pubmed
,
Xenbase
GODEFROI,
DL-1-(1-ARYLALKYL)IMIDAZOLE-5-CARBOXYLATE ESTERS. A NOVEL TYPE OF HYPNOTIC AGENTS.
1965,
Pubmed
Hill-Venning,
Subunit-dependent interaction of the general anaesthetic etomidate with the gamma-aminobutyric acid type A receptor.
1997,
Pubmed
,
Xenbase
Husain,
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.
2006,
Pubmed
,
Xenbase
Husain,
Synthesis and properties of 3-(2-hydroxyethyl)-3-n-pentyldiazirine, a photoactivable general anesthetic.
1999,
Pubmed
,
Xenbase
Husain,
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.
2003,
Pubmed
,
Xenbase
JONES,
The synthesis of 5-imidazolecarboxylates from glycine and substituted glycine esters.
1949,
Pubmed
Jurd,
General anesthetic actions in vivo strongly attenuated by a point mutation in the GABA(A) receptor beta3 subunit.
2003,
Pubmed
Li,
Identification of a GABAA receptor anesthetic binding site at subunit interfaces by photolabeling with an etomidate analog.
2006,
Pubmed
Liao,
R (+) etomidate and the photoactivable R (+) azietomidate have comparable anesthetic activity in wild-type mice and comparably decreased activity in mice with a N265M point mutation in the gamma-aminobutyric acid receptor beta3 subunit.
2005,
Pubmed
McGurk,
The effect of a transmembrane amino acid on etomidate sensitivity of an invertebrate GABA receptor.
1998,
Pubmed
,
Xenbase
Middleton,
Mapping of the acetylcholine binding site of the nicotinic acetylcholine receptor: [3H]nicotine as an agonist photoaffinity label.
1991,
Pubmed
Mihic,
Sites of alcohol and volatile anaesthetic action on GABA(A) and glycine receptors.
1997,
Pubmed
,
Xenbase
Nirthanan,
Identification of binding sites in the nicotinic acetylcholine receptor for TDBzl-etomidate, a photoreactive positive allosteric effector.
2008,
Pubmed
Pistis,
The interaction of general anaesthetics with recombinant GABAA and glycine receptors expressed in Xenopus laevis oocytes: a comparative study.
1997,
Pubmed
,
Xenbase
Reynolds,
Sedation and anesthesia mediated by distinct GABA(A) receptor isoforms.
2003,
Pubmed
Rosen,
Channel opening by anesthetics and GABA induces similar changes in the GABAA receptor M2 segment.
2007,
Pubmed
Rudolph,
Molecular and neuronal substrates for general anaesthetics.
2004,
Pubmed
Rüsch,
Gating allosterism at a single class of etomidate sites on alpha1beta2gamma2L GABA A receptors accounts for both direct activation and agonist modulation.
2004,
Pubmed
,
Xenbase
Sandermann,
Ecotoxicology of narcosis: stereoselectivity and potential target sites.
2008,
Pubmed
,
Xenbase
Shih,
A carbene-yielding amino acid for incorporation into peptide photoaffinity reagents.
1985,
Pubmed
Solt,
General anesthetic-induced channel gating enhancement of 5-hydroxytryptamine type 3 receptors depends on receptor subunit composition.
2005,
Pubmed
,
Xenbase
Stewart,
Tryptophan mutations at azi-etomidate photo-incorporation sites on alpha1 or beta2 subunits enhance GABAA receptor gating and reduce etomidate modulation.
2008,
Pubmed
,
Xenbase
Sullivan,
Mapping the agonist binding site of the nicotinic acetylcholine receptor. Orientation requirements for activation by covalent agonist.
2000,
Pubmed
,
Xenbase
Tomlin,
Stereoselective effects of etomidate optical isomers on gamma-aminobutyric acid type A receptors and animals.
1998,
Pubmed
Waki,
Efficient preparation of N alpha-formylamino acid tert-butyl esters.
1977,
Pubmed
Waud,
On biological assays involving quantal responses.
1972,
Pubmed
Ziebell,
Identification of binding sites in the nicotinic acetylcholine receptor for [3H]azietomidate, a photoactivatable general anesthetic.
2004,
Pubmed
Zolle,
New selective inhibitors of steroid 11beta-hydroxylation in the adrenal cortex. Synthesis and structure-activity relationship of potent etomidate analogues.
2008,
Pubmed
