Methoxycarbonyl-etomidate

Background Etomidate is a rapidly acting sedative-hypnotic that provides hemodynamic stability. It causes prolonged suppression of adrenocortical steroid synthesis; therefore, its clinical utility and safety are limited. The authors describe the results of studies to define the pharmacology of (R)-3-methoxy-3-oxopropyl1-(1-phenylethyl)-1H-imidazole-5-carboxylate (MOC-etomidate), the first etomidate analogue designed to be susceptible to ultra-rapid metabolism. Methods The gamma-aminobutyric acid type A receptor activities of MOC-etomidate and etomidate were compared by using electrophysiological techniques in human alpha1beta2gamma2l receptors. MOC-etomidate's hypnotic concentration was determined in tadpoles by using a loss of righting reflex assay. Its in vitro metabolic half-life was measured in human liver S9 fraction, and the resulting metabolite was provisionally identified by using high-performance liquid chromatography/mass spectrometry techniques. The hypnotic and hemodynamic actions of MOC-etomidate, etomidate, and propofol were defined in rats. The abilities of MOC-etomidate and etomidate to inhibit corticosterone production were assessed in rats. Results MOC-etomidate potently enhanced gamma-aminobutyric acid type A receptor function and produced loss of righting reflex in tadpoles. Metabolism in human liver S9 fraction was first-order, with an in vitro half-life of 4.4 min versus more than 40 min for etomidate. MOC-etomidate's only detectable metabolite was a carboxylic acid. In rats, MOC-etomidate produced rapid loss of righting reflex that was extremely brief and caused minimal hemodynamic changes. Unlike etomidate, MOC-etomidate produced no adrenocortical suppression 30 min after administration. Conclusions MOC-etomidate is an etomidate analogue that retains etomidate's important favorable pharmacological properties. However, it is rapidly metabolized, ultra-short-acting, and does not produce prolonged adrenocortical suppression after bolus administration.

Download Full-text

Faculty Opinions recommendation of Effect of isoflurane and other potent inhaled anesthetics on minimum alveolar concentration, learning, and the righting reflex in mice engineered to express alpha1 gamma-aminobutyric acid type A receptors unresponsive to isoflurane.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.1059787.511720 ◽

2007 ◽

Author(s):

M Bruce MacIver

Keyword(s):

Minimum Alveolar Concentration ◽

Type A ◽

Aminobutyric Acid ◽

Gamma Aminobutyric Acid ◽

Inhaled Anesthetics ◽

Acid Type ◽

Righting Reflex

Download Full-text

Faculty Opinions recommendation of Effect of isoflurane and other potent inhaled anesthetics on minimum alveolar concentration, learning, and the righting reflex in mice engineered to express alpha1 gamma-aminobutyric acid type A receptors unresponsive to isoflurane.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.1059787.518648 ◽

2007 ◽

Author(s):

Douglas Raines

Keyword(s):

Minimum Alveolar Concentration ◽

Type A ◽

Aminobutyric Acid ◽

Gamma Aminobutyric Acid ◽

Inhaled Anesthetics ◽

Acid Type ◽

Righting Reflex

Download Full-text

Analogues of Etomidate

Anesthesiology ◽

10.1097/aln.0000000000000268 ◽

2014 ◽

Vol 121 (2) ◽

pp. 290-301 ◽

Cited By ~ 25

Author(s):

Ervin Pejo ◽

Peter Santer ◽

Spencer Jeffrey ◽

Hilary Gallin ◽

S. Shaukat Husain ◽

...

Keyword(s):

Adrenocorticotropic Hormone ◽

Type A ◽

Chiral Center ◽

Aminobutyric Acid ◽

Adrenocortical Function ◽

Receptor Subtypes ◽

Structure Activity ◽

Acid Type ◽

Righting Reflex

Abstract Background: R-etomidate possesses unique desirable properties but potently suppresses adrenocortical function. Consequently, efforts are being made to define structure–activity relationships with the goal of designing analogues with reduced adrenocortical toxicity. The authors explored the pharmacological impact of modifying etomidate’s chiral center using R-etomidate, S-etomidate, and two achiral etomidate analogues (cyclopropyl etomidate and dihydrogen etomidate). Methods: The γ-aminobutyric acid type A receptor modulatory potencies of drugs were assessed in oocyte-expressed α1(L264T)β3γ2L and α1(L264T)β1γ2L γ-aminobutyric acid type A receptors (for each drug, n = 6 oocytes per subtype). In rats, hypnotic potencies and durations of action were measured using a righting reflex assay (n = 26 to 30 doses per drug), and adrenocortical potencies were quantified by using an adrenocorticotropic hormone stimulation test (n = 20 experiments per drug). Results: All four drugs activated both γ-aminobutyric acid type A receptor subtypes in vitro and produced hypnosis and suppressed adrenocortical function in rats. However, drug potencies in each model ranged by 1 to 2 orders of magnitude. R-etomidate had the highest γ-aminobutyric acid type A receptor modulatory, hypnotic, and adrenocortical inhibitory potencies. Respectively, R-etomidate, S-etomidate, and cyclopropyl etomidate were 27.4-, 18.9-, and 23.5-fold more potent activators of receptors containing β3 subunits than β1 subunits; however, dihydrogen etomidate’s subunit selectivity was only 2.48-fold and similar to that of propofol (2.08-fold). S-etomidate was 1/23rd as potent an adrenocortical inhibitor as R-etomidate. Conclusion: The linkage between the structure of etomidate’s chiral center and its pharmacology suggests that altering etomidate’s chiral center may be used as part of a strategy to design analogues with more desirable adrenocortical activities and/or subunit selectivities.

Download Full-text

Carboetomidate

Anesthesiology ◽

10.1097/aln.0b013e3181cf40ed ◽

2010 ◽

Vol 112 (3) ◽

pp. 637-644 ◽

Cited By ~ 61

Author(s):

Joseph F. Cotten ◽

Stuart A. Forman ◽

Joydev K. Laha ◽

Gregory D. Cuny ◽

S. Shaukat Husain ◽

...

Keyword(s):

Critically Ill ◽

Critically Ill Patients ◽

Type A ◽

Aminobutyric Acid ◽

Adrenocortical Function ◽

Gamma Aminobutyric Acid ◽

Wild Type ◽

High Affinity ◽

Acid Type

Background Etomidate is a sedative hypnotic that is often used in critically ill patients because it provides superior hemodynamic stability. However, it also binds with high affinity to 11beta-hydroxylase, potently suppressing the synthesis of steroids by the adrenal gland that are necessary for survival. The authors report the results of studies to define the pharmacology of (R)-ethyl 1-(1-phenylethyl)-1H-pyrrole-2-carboxylate (carboetomidate), a pyrrole analog of etomidate specifically designed not to bind with high affinity to 11beta-hydroxylase. Methods The hypnotic potency of carboetomidate was defined in tadpoles and rats using loss of righting reflex assays. Its ability to enhance wild-type alpha1beta2gamma2l and etomidate-insensitive mutant alpha1beta2M286Wgamma2l human gamma-aminobutyric acid type A receptor activities was assessed using electrophysiologic techniques. Its potency for inhibiting in vitro cortisol synthesis was defined using a human adrenocortical cell assay. Its effects on in vivo hemodynamic and adrenocortical function were defined in rats. Results Carboetomidate was a potent hypnotic in tadpoles and rats. It increased currents mediated by wild-type but not etomidate-insensitive mutant gamma-aminobutyric acid type A receptors. Carboetomidate was a three orders of magnitude less-potent inhibitor of in vitro cortisol synthesis by adrenocortical cells than was etomidate. In rats, carboetomidate caused minimal hemodynamic changes and did not suppress adrenocortical function at hypnotic doses. Conclusions Carboetomidate is an etomidate analog that retains many beneficial properties of etomidate, but it is dramatically less potent as an inhibitor of adrenocortical steroid synthesis. Carboetomidate is a promising new sedative hypnotic for potential use in critically ill patients in whom adrenocortical suppression is undesirable.

Download Full-text

Preparation of Barbiturate Optical Isomers and Their Effects on GABA (A) Receptors

Anesthesiology ◽

10.1097/00000542-199906000-00029 ◽

1999 ◽

Vol 90 (6) ◽

pp. 1714-1722. ◽

Cited By ~ 30

Author(s):

Sarah L. Tomlin ◽

Andrew Jenkins ◽

William R. Lieb ◽

Nicholas P. Franks

Keyword(s):

Rank Order ◽

Type A ◽

Mouse Fibroblast ◽

Aminobutyric Acid ◽

Optical Isomers ◽

Gamma Aminobutyric Acid ◽

Patch Clamp Technique ◽

Acid Type ◽

Induced Currents

Background Barbiturate anesthetics are optically active and usually exist in two mirror-image enantiomeric forms. Their stereoselective effects in mammals are well known, but remarkably few data are available concerning their effects on anesthetic targets in vitro. This is in part because of the lack of availability of pure barbiturate enantiomers. Such in vitro data could be used to test the relevance of putative molecular targets. Methods A high-performance liquid chromatography technique using a permethylated beta-cyclodextrin column was used to separate the optical isomers of three barbiturates in preparative quantities. The effects of the isomers on GABA-induced currents in stably transfected mouse fibroblast cells were investigated using the whole-cell patch-clamp technique. Results Highly purified optical isomers of hexobarbital, pentobarbital, and thiopental were prepared, and their effects were studied on a gamma-aminobutyric acid type A receptor of defined subunit composition. For each of the three barbiturates, both enantiomers potentiated gamma-aminobutyric acid-induced currents at pharmacologically relevant concentrations, with the S-enantiomer being more potent than the R-enantiomer by a factor of between 1.7 and 3.5. The degree of stereoselectivity did not vary greatly with anesthetic concentration. Conclusions The rank order and degree of stereoselectivity that we have observed for the enantiomers of hexobarbital, pentobarbital, and thiopental acting on the gamma-aminobutyric acid type A receptor are entirely consistent with this receptor playing a central role in the anesthetic actions of barbiturates.

Download Full-text