In Vivo and In Vitro Pharmacological Studies of Methoxycarbonyl-Carboetomidate

Pejo, Ervin; Cotten, Joseph F.; Kelly, Elizabeth; Ge, Ri Le; Cuny, Gregory D.; Laha, Joydev K.; Liu, Jifeng; Lin, Xiang; Raines, Douglas E.

doi:10.1213/ane.0b013e3182320559

Cited by 53 publications

(42 citation statements)

References 17 publications

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“…38 For all studies of GABA potentiation, a GABA concentration-peak current response curve was generated for each oocyte to define the GABA concentration that elicits either 5% or 50% of the current evoked by 1 mM GABA (i.e. EC 5 GABA or EC 50 GABA, respectively).…”

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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“…Electrophysiological recordings were performed at room temperature using the whole cell two-electrode voltage-clamp technique as previously described. 20 In each experiment, the peak amplitude was defined as the difference between the baseline current prior to etomidate analogue infusion and the single highest point in the current trace during infusion. This amplitude was then normalized to the peak amplitude measured in control currents elicited by 100 μM GABA (a concentration of GABA that maximally activates GABA A receptors) in the same oocyte.…”

Section: Methodsmentioning

confidence: 99%

“…13,17–20 These compounds include etomidate esters that are ultra-rapidly metabolized, pyrrole analogues devoid of adrenocortical side effects, and achiral analogues with reduced hypnotic and adrenocortical inhibitory potencies. Although it seems likely that only a handful of these analogues have potential value as clinical anesthetic agents, together they can be used as pharmacological tools for structure-activity relationship studies to better define the structural determinants of etomidate’s enhancing action on the GABA A receptor.…”

Section: Introductionmentioning

confidence: 99%

γ-Aminobutyric Acid Type A Receptor Modulation by Etomidate Analogs

Pejo

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.

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“…Recently approved agents such as fospropofol (Lusedra 1 ) and sugammadex (Bridion 1 in the EU) only offer modest clinical advances. Other promising new drugs under active development in this field are structural analogs of known compounds with similar mechanisms of action [9][10][11]. Lack of originality in drug development in the field led one expert to wonder why anesthesiologists have moved away from the model of innovative 'clinical pharmacologists' [12].…”

Section: Introductionmentioning

confidence: 99%