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dc.contributor.authorHusain, S Shaukat
dc.contributor.authorNirthanan, Selvanayagam
dc.contributor.authorRuesch, Dirk
dc.contributor.authorSolt, Ken
dc.contributor.authorCheng, Qi
dc.contributor.authorLi, Guo-Dong
dc.contributor.authorArevalo, Enrique
dc.contributor.authorOlsen, Richard W
dc.contributor.authorRaines, Douglas E
dc.contributor.authorForman, Stuart A
dc.contributor.authorCohen, Jonathan B
dc.contributor.authorMiller, Keith W
dc.date.accessioned2017-05-03T15:28:59Z
dc.date.available2017-05-03T15:28:59Z
dc.date.issued2006
dc.date.modified2009-09-28T06:52:24Z
dc.identifier.issn0022-2623
dc.identifier.doi10.1021/jm051207b
dc.identifier.urihttp://hdl.handle.net/10072/25850
dc.description.abstractTo 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general anesthetic etomidate (2-ethyl 1-(phenylethyl)-1H-imidazole-5-carboxylate), in which the 2-ethyl group has been replaced by photoactivable groups based on either aryl diazirine or benzophenone chemistry, have been synthesized and characterized pharmacologically.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.
dc.description.peerreviewedYes
dc.description.publicationstatusYes
dc.languageEnglish
dc.language.isoeng
dc.publisherAmerican Chemical Society
dc.publisher.placeWashington, DC
dc.relation.ispartofstudentpublicationN
dc.relation.ispartofpagefrom4818
dc.relation.ispartofpageto4825
dc.relation.ispartofissue16
dc.relation.ispartofjournalJournal of Medicinal Chemistry
dc.relation.ispartofvolume49
dc.rights.retentionY
dc.subject.fieldofresearchMedicinal and biomolecular chemistry
dc.subject.fieldofresearchOrganic chemistry
dc.subject.fieldofresearchCentral nervous system
dc.subject.fieldofresearchPharmacology and pharmaceutical sciences
dc.subject.fieldofresearchPharmaceutical sciences
dc.subject.fieldofresearchcode3404
dc.subject.fieldofresearchcode3405
dc.subject.fieldofresearchcode320903
dc.subject.fieldofresearchcode3214
dc.subject.fieldofresearchcode321405
dc.titleSynthesis of Trifluoromethylaryl Diazirine and Benzophenone Derivatives of Etomidate that Are Potent General Anesthetics and Effective Photolabels for Probing Sites on Ligand-Gated Ion Channels
dc.typeJournal article
dc.type.descriptionC1 - Articles
dc.type.codeC - Journal Articles
gro.date.issued2006
gro.hasfulltextNo Full Text
gro.griffith.authorNirthanan, Niru


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