Click here to close
Hello! We notice that you are using Internet Explorer, which is not supported by Xenbase and may cause the site to display incorrectly.
We suggest using a current version of Chrome,
FireFox, or Safari.
Anesthesiology
2017 Nov 01;1275:824-837. doi: 10.1097/ALN.0000000000001840.
Show Gene links
Show Anatomy links
Competitive Antagonism of Anesthetic Action at the γ-Aminobutyric Acid Type A Receptor by a Novel Etomidate Analog with Low Intrinsic Efficacy.
Ma C
,
Pejo E
,
McGrath M
,
Jayakar SS
,
Zhou X
,
Miller KW
,
Cohen JB
,
Raines DE
.
???displayArticle.abstract???
BACKGROUND: The authors characterized the γ-aminobutyric acid type A receptor pharmacology of the novel etomidate analog naphthalene-etomidate, a potential lead compound for the development of anesthetic-selective competitive antagonists.
METHODS: The positive modulatory potencies and efficacies of etomidate and naphthalene-etomidate were defined in oocyte-expressed α1β3γ2L γ-aminobutyric acid type A receptors using voltage clamp electrophysiology. Using the same technique, the ability of naphthalene-etomidate to reduce currents evoked by γ-aminobutyric acid alone or γ-aminobutyric acid potentiated by etomidate, propofol, pentobarbital, and diazepam was quantified. The binding affinity of naphthalene-etomidate to the transmembrane anesthetic binding sites of the γ-aminobutyric acid type A receptor was determined from its ability to inhibit receptor photoaffinity labeling by the site-selective photolabels [H]azi-etomidate and R-[H]5-allyl-1-methyl-5-(m-trifluoromethyl-diazirynylphenyl) barbituric acid.
RESULTS: In contrast to etomidate, naphthalene-etomidate only weakly potentiated γ-aminobutyric acid-evoked currents and induced little direct activation even at a near-saturating aqueous concentration. It inhibited labeling of γ-aminobutyric acid type A receptors by [H]azi-etomidate and R-[H]5-allyl-1-methyl-5-(m-trifluoromethyl-diazirynylphenyl) barbituric acid with similar half-maximal inhibitory concentrations of 48 μM (95% CI, 28 to 81 μM) and 33 μM (95% CI, 20 to 54 μM). It also reduced the positive modulatory actions of anesthetics (propofol > etomidate ~ pentobarbital) but not those of γ-aminobutyric acid or diazepam. At 300 μM, naphthalene-etomidate increased the half-maximal potentiating propofol concentration from 6.0 μM (95% CI, 4.4 to 8.0 μM) to 36 μM (95% CI, 17 to 78 μM) without affecting the maximal response obtained at high propofol concentrations.
CONCLUSIONS: Naphthalene-etomidate is a very low-efficacy etomidate analog that exhibits the pharmacology of an anesthetic competitive antagonist at the γ-aminobutyric acid type A receptor.
Ahn,
Role of GABA Deficit in Sensitivity to the Psychotomimetic Effects of Amphetamine.
2015, Pubmed
Ahn,
Role of GABA Deficit in Sensitivity to the Psychotomimetic Effects of Amphetamine.
2015,
Pubmed
Belelli,
Extrasynaptic GABAA receptors of thalamocortical neurons: a molecular target for hypnotics.
2005,
Pubmed
Belelli,
The in vitro and in vivo enantioselectivity of etomidate implicates the GABAA receptor in general anaesthesia.
2003,
Pubmed
,
Xenbase
Brull,
Current Status of Neuromuscular Reversal and Monitoring: Challenges and Opportunities.
2017,
Pubmed
Chang,
Allosteric activation mechanism of the alpha 1 beta 2 gamma 2 gamma-aminobutyric acid type A receptor revealed by mutation of the conserved M2 leucine.
1999,
Pubmed
,
Xenbase
Changeux,
50 years of allosteric interactions: the twists and turns of the models.
2013,
Pubmed
Chemali,
Active emergence from propofol general anesthesia is induced by methylphenidate.
2012,
Pubmed
Cheng,
Alpha5GABAA receptors mediate the amnestic but not sedative-hypnotic effects of the general anesthetic etomidate.
2006,
Pubmed
Chiara,
Specificity of intersubunit general anesthetic-binding sites in the transmembrane domain of the human α1β3γ2 γ-aminobutyric acid type A (GABAA) receptor.
2013,
Pubmed
Chiara,
Mapping general anesthetic binding site(s) in human α1β3 γ-aminobutyric acid type A receptors with [³H]TDBzl-etomidate, a photoreactive etomidate analogue.
2012,
Pubmed
Dostalova,
High-level expression and purification of Cys-loop ligand-gated ion channels in a tetracycline-inducible stable mammalian cell line: GABAA and serotonin receptors.
2010,
Pubmed
Forman,
Monod-Wyman-Changeux allosteric mechanisms of action and the pharmacology of etomidate.
2012,
Pubmed
Franks,
Molecular targets underlying general anaesthesia.
2006,
Pubmed
Franks,
Which molecular targets are most relevant to general anaesthesia?
1998,
Pubmed
GALE,
The effect of methylphenidate (ritalin) on thiopental recovery.
1958,
Pubmed
Ge,
The pharmacology of cyclopropyl-methoxycarbonyl metomidate: a comparison with propofol.
2014,
Pubmed
,
Xenbase
Ge,
Pharmacological studies of methoxycarbonyl etomidate's carboxylic acid metabolite.
2012,
Pubmed
,
Xenbase
Guitchounts,
Two etomidate sites in α1β2γ2 γ-aminobutyric acid type A receptors contribute equally and noncooperatively to modulation of channel gating.
2012,
Pubmed
,
Xenbase
Hill-Venning,
Subunit-dependent interaction of the general anaesthetic etomidate with the gamma-aminobutyric acid type A receptor.
1997,
Pubmed
,
Xenbase
Husain,
2-(3-Methyl-3H-diaziren-3-yl)ethyl 1-(1-phenylethyl)-1H-imidazole-5-carboxylate: a derivative of the stereoselective general anesthetic etomidate for photolabeling ligand-gated ion channels.
2003,
Pubmed
,
Xenbase
Jayakar,
Positive and Negative Allosteric Modulation of an α1β3γ2 γ-Aminobutyric Acid Type A (GABAA) Receptor by Binding to a Site in the Transmembrane Domain at the γ+-β- Interface.
2015,
Pubmed
Jurd,
General anesthetic actions in vivo strongly attenuated by a point mutation in the GABA(A) receptor beta3 subunit.
2003,
Pubmed
Kakisis,
Protamine Reduces Bleeding Complications without Increasing the Risk of Stroke after Carotid Endarterectomy: A Meta-analysis.
2016,
Pubmed
Kaufman,
Biophysical mechanisms of anesthetic action: historical perspective and review of current concepts.
1977,
Pubmed
Krasowski,
Propofol and other intravenous anesthetics have sites of action on the gamma-aminobutyric acid type A receptor distinct from that for isoflurane.
1998,
Pubmed
Li,
Identification of a GABAA receptor anesthetic binding site at subunit interfaces by photolabeling with an etomidate analog.
2006,
Pubmed
Matubayasi,
Is membrane expansion relevant to anesthesia? Mean excess volume.
1983,
Pubmed
Miller,
Site of action of general anaesthetics.
1965,
Pubmed
Miller,
General anaesthetics can selectively perturb lipid bilayer membranes.
1976,
Pubmed
Möhler,
Agonist and antagonist benzodiazepine receptor interaction in vitro.
1981,
Pubmed
North,
Contrasting membrane localization and behavior of halogenated cyclobutanes that follow or violate the Meyer-Overton hypothesis of general anesthetic potency.
1997,
Pubmed
Pani,
Reversal agents in anaesthesia and critical care.
2015,
Pubmed
Pejo,
γ-Aminobutyric Acid Type A Receptor Modulation by Etomidate Analogs.
2016,
Pubmed
,
Xenbase
Pejo,
Analogues of etomidate: modifications around etomidate's chiral carbon and the impact on in vitro and in vivo pharmacology.
2014,
Pubmed
,
Xenbase
Pejo,
In vivo and in vitro pharmacological studies of methoxycarbonyl-carboetomidate.
2012,
Pubmed
,
Xenbase
Perouansky,
Coagulation, flocculation, and denaturation: a century of research into protoplasmic theories of anesthesia.
2014,
Pubmed
Pert,
Properties of opiate-receptor binding in rat brain.
1973,
Pubmed
Plourde,
Antagonism of sevoflurane anaesthesia by physostigmine: effects on the auditory steady-state response and bispectral index.
2003,
Pubmed
Raines,
The enhancement of proton/hydroxyl flow across lipid vesicles by inhalation anesthetics.
1989,
Pubmed
Rudolph,
Molecular and neuronal substrates for general anaesthetics.
2004,
Pubmed
Ruesch,
An allosteric coagonist model for propofol effects on α1β2γ2L γ-aminobutyric acid type A receptors.
2012,
Pubmed
,
Xenbase
Rüsch,
Classic benzodiazepines modulate the open-close equilibrium in alpha1beta2gamma2L gamma-aminobutyric acid type A receptors.
2005,
Pubmed
,
Xenbase
Rüsch,
Gating allosterism at a single class of etomidate sites on alpha1beta2gamma2L GABA A receptors accounts for both direct activation and agonist modulation.
2004,
Pubmed
,
Xenbase
Savechenkov,
Allyl m-trifluoromethyldiazirine mephobarbital: an unusually potent enantioselective and photoreactive barbiturate general anesthetic.
2012,
Pubmed
Sigel,
The benzodiazepine binding site of GABAA receptors.
1997,
Pubmed
Simon,
Stereospecific binding of the potent narcotic analgesic (3H) Etorphine to rat-brain homogenate.
1973,
Pubmed
Sivilotti,
Flumazenil, naloxone and the 'coma cocktail'.
2016,
Pubmed
Smith,
Functional domains of GABAA receptors.
1995,
Pubmed
Solt,
Correlating the clinical actions and molecular mechanisms of general anesthetics.
2007,
Pubmed
Srivastava,
Reversal of neuromuscular block.
2009,
Pubmed
Stewart,
Mutations at beta N265 in γ-aminobutyric acid type A receptors alter both binding affinity and efficacy of potent anesthetics.
2014,
Pubmed
,
Xenbase
WAINE,
Thiopentone anaesthesia terminated by bemegride.
1958,
Pubmed
Walters,
Benzodiazepines act on GABAA receptors via two distinct and separable mechanisms.
2000,
Pubmed
,
Xenbase
Zarnowska,
Etomidate blocks LTP and impairs learning but does not enhance tonic inhibition in mice carrying the N265M point mutation in the beta3 subunit of the GABA(A) receptor.
2015,
Pubmed
Ziemba,
Correction for Inhibition Leads to an Allosteric Co-Agonist Model for Pentobarbital Modulation and Activation of α1β3γ2L GABAA Receptors.
2016,
Pubmed
,
Xenbase
