Pharmacological Studies of Methoxycarbonyl Etomidate's Carboxylic Acid Metabolite

McGrath³

et al. 2017

Anesthesiology

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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 [3H]azi-etomidate and R-[3H]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 [3H]azi-etomidate and R-[3H]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.

Section: Methodsmentioning

confidence: 99%

Competitive Antagonism of Anesthetic Action at the γ-Aminobutyric Acid Type A Receptor by a Novel Etomidate Analog with Low Intrinsic Efficacy

McGrath³

et al. 2017

Anesthesiology

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“…We incorporated a channel mutation into the receptor that stabilizes its open state, thus increasing anesthetic sensitivity and allowing more complete anesthetic concentration-response curves to be generated (1) before reaching aqueous saturation at high anesthetic concentrations and (2) without the potentially confounding effects of a co-administered agonist. 10,13,21 We also defined the potencies with which etomidate analogues produce hypnosis in rats. We then used computational techniques to build statistical and graphical models that relate the GABA A receptor and hypnotic potencies of these etomidate analogues to their physical structures (i.e.…”

Section: Introductionmentioning

confidence: 99%

γ-Aminobutyric Acid Type A Receptor Modulation by Etomidate Analogs

Santer

Wang³

et al. 2016

Anesthesiology

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Background Etomidate is a highly potent anesthetic agent that is believed to produce hypnosis by enhancing γ-aminobutyric acid type A (GABAA) receptor function. The authors characterized the GABAA receptor and hypnotic potencies of etomidate analogs. The authors then used computational techniques to build statistical and graphical models that relate the potencies of these etomidate analogs to their structures to identify the specific molecular determinants of potency. Methods GABAA receptor potencies were defined with voltage clamp electrophysiology using α1β3γ2 receptors harboring a channel mutation (α1[L264T]) that enhances anesthetic sensitivity (n = 36 to 60 measurements per concentration–response curve). The hypnotic potencies of etomidate analogs were defined using a loss of righting reflexes assay in Sprague Dawley rats (n = 9 to 21 measurements per dose–response curve). Three-dimensional quantitative structure–activity relationships were determined in silico using comparative molecular field analysis. Results The GABAA receptor and hypnotic potencies of etomidate and the etomidate analogs ranged by 91- and 53-fold, respectively. These potency measurements were significantly correlated (r2 = 0.72), but neither measurement correlated with drug hydrophobicity (r2 = 0.019 and 0.005, respectively). Statistically significant and predictive comparative molecular field analysis models were generated, and a pharmacophore model was built that revealed both the structural elements in etomidate analogs associated with high potency and the interactions that these elements make with the etomidate-binding site. Conclusions There are multiple specific structural elements in etomidate and etomidate analogs that mediate GABAA receptor modulation. Modifying any one element can alter receptor potency by an order of magnitude or more.

“…5 As previously reported, we incorporate the L264T ion channel mutation into the receptor because it stabilizes the receptor’s open state, thus increasing anesthetic sensitivity and allowing more complete anesthetic concentration-response curves to be generated before reaching aqueous saturation at high anesthetic concentrations and without the potentially confounding effects of a co-administered agonist. 13–15 Oocytes were then incubated in ND96 buffer (96 mM NaCl, 2 mM KCl, 1.8 mM CaCl 2 , 1 mM MgCl 2 , 5 mM HEPES, pH=7.4) containing 0.05 mg/mL of gentamicin for at least 18 hours at 18°C before study.…”

Section: Methodsmentioning

confidence: 99%

“…Data reported for MOC-etomidate, MOC-ECA, and CPMM, are from previously published studies by our laboratory using the same approach. 5,12,15 …”

Section: Methodsmentioning

confidence: 99%

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Distinct Hypnotic Recoveries After Infusions of Methoxycarbonyl Etomidate and Cyclopropyl Methoxycarbonyl Metomidate

Anesthesia &Amp; Analgesia

Liu²,

Lin³

et al. 2016

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Background Methoxycarbonyl etomidate (MOC-etomidate) and cyclopropyl methoxycarbonyl metomidate (CPMM) are rapidly metabolized “soft” etomidate analogues. CPMM’s duration of hypnotic effect is context-insensitive whereas MOC-etomidate’s is not. In the current study, we tested the hypothesis that CPMM’s effect is context-insensitive because, unlike MOC-etomidate, its metabolite fails to reach physiologically important concentrations in vivo even with prolonged continuous infusion. Methods We compared the potencies with which MOC-etomidate and CPMM activate α1(L264T)β3γ2 gamma-aminobutyric acid type A receptors and induce loss-of-righting reflexes (i.e. produce hypnosis) in tadpoles with those of their metabolites (MOC-ECA and CPMM-CA, respectively). We measured metabolite concentrations in blood and cerebrospinal fluid of Sprague Dawley rats upon CPMM infusion and compared them to those achieved with MOC-etomidate infusion. We measured the rates with which brain tissue from Sprague Dawley rats metabolize MOC-etomidate and CPMM. Results Both analogues and their metabolites enhanced gamma-aminobutyric acid type A receptor function and induced loss-of-righting reflexes in a concentration-dependent manner. However in these 2 assays, CPMM-CA’s potency relative to its parent hypnotic was approximately 1:4,900 and 1:1,900, respectively, whereas MOC-ECA’s was only approximately 1:415 and 1:390, respectively. With 2-hr CPMM infusions, CPMM-CA reached respective concentrations in the blood and cerebrospinal fluid that were 2 and >3 orders of magnitude lower than that which produced hypnosis. CPMM was metabolized by brain tissue at a rate that is approximately 1/15th that of MOC-etomidate. Conclusions Hypnotic recovery after CPMM administration is context-insensitive because its metabolite does not accumulate to hypnotic levels in the central nervous system. This reflects the very large potency ratio between CPMM and its carboxylic acid metabolite CPMM-CA and the resistance of CPMM to metabolism by esterases present in the brain.