The Pharmacology of Cyclopropyl-Methoxycarbonyl Metomidate

Ge, Rile; Pejo, Ervin; Gallin, Hilary; Jeffrey, Spencer; Cotten, Joseph F.; Raines, Douglas E.

doi:10.1213/ane.0000000000000069

Cited by 27 publications

(18 citation statements)

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“…Sample sizes (4 – 6 points per drug concentration for electrophysiological experiments) were defined based on our previous experience. 29,30,47,48 A one-sample t test (two tailed) was used to statistically assess whether 300 μM naphthalene-etomidate significantly changed peak currents evoked by EC 50 GABA or EC 5 GABA potentiated by each of the PAMs. The statistical comparisons between the EC 50 s for propofol potentiation of EC 5 GABA-evoked currents in the presence versus absence of 300 μM naphthalene-etomidate, and those between naphthalene-etomidate potency for inhibiting photolabeling by [ 3 H]azi- etomidate versus R-[ 3 H] m TFD-MPAB were made using the extra sum-of-squares F test.…”

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

Pejo

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.

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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

Pejo

McGrath³

et al. 2017

Anesthesiology

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“…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%

“…CPMM-CA was approximately 4,900-fold less potent than was CPMM. Data for CPMM were taken from Reference 12. In both panels, each data point is the mean value (± SD) derived from 6 oocyte experiments.…”

Section: Figurementioning

confidence: 99%

“…In both panels, each data point was obtained using 5 tadpoles. Data for MOC-etomidate and MOC-ECA were from Reference 15 and that for CPMM were from Reference 12.…”

Section: Figurementioning

confidence: 99%

“…5–12 Our primarily goal was to create a drug that would retain etomidate’s highly desirable properties, but whose effects on adrenocortical function would lift quickly after drug administration because the drug was rapidly eliminated. At the same time, it was hoped that recovery from the drug’s hypnotic action would similarly be very rapid even after prolonged infusion.…”

Section: Introductionmentioning

confidence: 99%

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

Pejo

Liu²,

Lin³

et al. 2016

Anesthesia &Amp; Analgesia

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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.

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Etomidate and Etomidate Analogues: Molecular Pharmacology and Behavioral Actions

Raines

2017

Total Intravenous Anesthesia and Target Controlled Infusions

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The Pharmacology of Cyclopropyl-Methoxycarbonyl Metomidate

Abstract: CPMM and propofol have similar potencies in GABAA receptors and tadpoles; however, CPMM provides more rapid and predictable recovery than propofol, particularly after prolonged infusion.

Cited by 27 publications

References 18 publications

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

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

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

Etomidate and Etomidate Analogues: Molecular Pharmacology and Behavioral Actions

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