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.
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general anesthetic etomidate (2-ethyl 1-(phenylethyl)-1H-imidazole-5-carboxylate), in which the 2-ethyl group has been replaced by photoactivable groups based on either aryl diazirine or benzophenone chemistry, have been synthesized and characterized pharmacologically.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.
Husain
S Shaukat
SS
Department of Anesthesia and Critical Care, Massachusetts General Hospital, Boston, Massachusetts 02114 USA.
Nirthanan
Selvanayagam
S
Ruesch
Dirk
D
Solt
Ken
K
Cheng
Qi
Q
Li
Guo-Dong
GD
Arevalo
Enrique
E
Olsen
Richard W
RW
Raines
Douglas E
DE
Forman
Stuart A
SA
Cohen
Jonathan B
JB
Miller
Keith W
KW
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
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