p-Trifluoromethyldiazirinyl-etomidate: a potent photoreactive general anesthetic derivative of etomidate that is selective for ligand-gated cationic ion channels.
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.
Husain
S Shaukat
SS
Department of Anesthesia, Critical Care and Pain Medicine, Massachusetts General Hospital, 32 Fruit Street, Boston, Massachusetts 02114, USA.
Stewart
Deirdre
D
Desai
Rooma
R
Hamouda
Ayman K
AK
Li
S Guo-Dong
SG
Kelly
Elizabeth
E
Dostalova
Zuzana
Z
Zhou
Xiaojuan
X
Cotten
Joseph F
JF
Raines
Douglas E
DE
Olsen
Richard W
RW
Cohen
Jonathan B
JB
Forman
Stuart A
SA
Miller
Keith W
KW
D000494:Allosteric Regulation; D018681:Anesthetics, General / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D000818:Animals; D002417:Cattle; D002540:Cerebral Cortex / Q000378:metabolism; D003978:Diazomethane / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D005045:Etomidate / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D005260:Female; D066298:In Vitro Techniques; D015640:Ion Channel Gating; D007473:Ion Channels / Q000502:physiology*; D007814:Larva; D008024:Ligands; D008027:Light; D016297:Mutagenesis, Site-Directed; D018733:Nicotinic Antagonists / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D009865:Oocytes / Q000187:drug effects / Q000502:physiology; D019920:Photoaffinity Labels / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D021122:Protein Subunits / Q000502:physiology; D011869:Radioligand Assay; D011963:Receptors, GABA-A / Q000235:genetics / Q000502:physiology; D011978:Receptors, Nicotinic / Q000502:physiology; D044406:Receptors, Serotonin, 5-HT3 / Q000502:physiology; D058831:Serotonin 5-HT3 Receptor Antagonists; D012995:Solubility; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D014101:Torpedo; D014982:Xenopus laevis; D005680:gamma-Aminobutyric Acid / Q000494:pharmacology
D018681:Anesthetics, General; D007473:Ion Channels; D008024:Ligands; D018733:Nicotinic Antagonists; D019920:Photoaffinity Labels; D021122:Protein Subunits; D011963:Receptors, GABA-A; D011978:Receptors, Nicotinic; D044406:Receptors, Serotonin, 5-HT3; D058831:Serotonin 5-HT3 Receptor Antagonists; C552339:ethyl 1-(1-(4-(3-(trifluoromethyl)-3H-diazirin-3-yl)phenyl)ethyl)-1H-imidazole-5-carboxylate; D005680:gamma-Aminobutyric Acid; D003978:Diazomethane; D005045:Etomidate