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

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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
Author Husain, S. Shaukat; Nirthanan, S. Niru; Ruesch, Dirk; Solt, Ken; Cheng, Qi; Li, Guo-Dong; Arevalo, Enrique; Olsen, Richard W.; Raines, Douglas E.; Forman, Stuart A.; Cohen, Jonathan B.; Miller, Keith W.
Journal Name Journal of Medicinal Chemistry
Year Published 2006
Place of publication Washington, DC
Publisher American Chemical Society
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general anesthetic etomidate (2-ethyl 1-(phenylethyl)-1H-imidazole-5-carboxylate), in which the 2-ethyl group has been replaced by photoactivable groups based on either aryl diazirine or benzophenone chemistry, have been synthesized and characterized pharmacologically.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.
Peer Reviewed Yes
Published Yes
Alternative URI http://dx.doi.org/10.1021/jm051207b
Volume 49
Issue Number 16
Page from 4818
Page to 4825
ISSN 0022-2623
Date Accessioned 2009-07-09
Language en_AU
Research Centre Griffith Health Institute
Faculty Griffith Health Faculty
Subject Central Nervous System; Pharmaceutical Sciences
URI http://hdl.handle.net/10072/25850
Publication Type Journal Articles (Refereed Article)
Publication Type Code c1x

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