Analogues of Etomidate

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. We explored the pharmacological impact of modifying etomidate’s chiral center utilizing R-etomidate, S-etomidate and two achiral etomidate analogues (cyclopropyl etomidate and dihydrogen etomidate). Methods The γ-aminobutyric acid type A (GABAA) receptor modulatory potencies of drugs were assessed in oocyte-expressed α1(L264T)β3γ2L and α1(L264T)β1γ2L GABAA 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 – 30 doses per drug) and adrenocortical potencies were quantified using an adrenocorticotropic hormone stimulation test (n = 20 experiments per drug). Results All four drugs activated both GABAA receptor subtypes in vitro and produced hypnosis and suppressed adrenocortical function in rats. However, drug potencies in each model ranged by 1–2 orders of magnitude. R-etomidate had the highest GABAA receptor moulatory, hypnotic, and adrenocortical inhibitory potencies. Respectively, R-etomidate, S-etomidate and cyclopropyl etomidate were 27.4-fold, 18.9-fold, 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.

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

“…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.…”

γ-Aminobutyric Acid Type A Receptor Modulation by Etomidate Analogs

“…10–12 In addition to enhancing GABA A receptor function, etomidate, etomidate analogues, and other anesthetics can inhibit the receptor’s function. 13–15 This inhibitory action typically occurs only at very high anesthetic concentrations and is likely mediated by a site that is distinct from that which produces enhancement.…”

“…Although etomidate’s enantiomers have identical physical properties, they differ by 1–2 orders of magnitude in their in vitro affinities and potencies for the GABA A receptor and, consequently, their in vivo hypnotic potencies. 3,13,16 Other small structural modifications around the chiral center similarly impact GABA A receptor and hypnotic potencies, implying that this region of etomidate’s molecular scaffold is a critical determinant of pharmacological activity. 13 The pharmacological importance of other regions is unknown.…”

“…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.…”

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

“…14 Peak current amplitudes elicited by a 30 second application of the desired compound were normalized to control currents elicited by 100 μM GABA in the same oocyte. For each compound, the concentration-mean peak current response data were fit to a Hill equation with minima and maxima constrained to 0% and 100%, respectively, to obtain the median effective concentration (EC 50 ) for direct activation of GABA A receptors.…”