Competitive Interactions Between Propofol and Diazepam: Studies in GABA Receptors and Zebrafish.

Although propofol is among the most commonly administered general anesthetics, its mechanism of action is not fully understood. It has been hypothesized that propofol acts via a similar mechanism as (R)-ethyl 1-(1-phenylethyl)-1H-imidazole-5-carboxylate (etomidate) by binding within the GABA receptor transmembrane receptor domain at the two / subunit interfaces with resultant positive allosteric modulation. To test this hypothesis, we leveraged the ability of diazepam to bind to those sites and act as a competitive antagonist.

Pharmacological management of severe Cushing's syndrome: the role of etomidate.

Cushing's syndrome (CS) is an endocrine disease characterized by excessive adrenocortical steroid production. One of the mainstay pharmacological treatments for CS are steroidogenesis enzyme inhibitors, including the antifungal agent ketoconazole along with metyrapone, mitotane, and aminoglutethimide. Recently, osilodrostat was added to this drug class and approved by the US Food and Drug Administration (FDA) for the treatment of Cushing's Disease.

Selective actions of benzodiazepines at the transmembrane anaesthetic binding sites of the GABA receptor: In vitro and in vivo studies.

Background And Purpose: In addition to binding to the classical high-affinity extracellular benzodiazepine binding site of the GABA receptor, some benzodiazepines occupy transmembrane inter-subunit anaesthetic sites that bind etomidate (β /α sites) or the barbiturate derivative R-mTFD-MPAB (α /β and γ /β sites). We aimed to define the functional effects of these interactions on GABA receptor activity and animal behaviour.

Experimental Approach: With flumazenil blocking classical high-affinity extracellular benzodiazepine site effects, modulation of GABA-activated currents by diazepam, midazolam and flurazepam was measured electrophysiologically in wildtype and M2-15' mutant α β γ GABA receptors.

Competitive Antagonism of Etomidate Action by Diazepam: In Vitro GABAA Receptor and In Vivo Zebrafish Studies.

Background: Recent cryo-electron microscopic imaging studies have shown that in addition to binding to the classical extracellular benzodiazepine binding site of the α1β3γ2L γ-aminobutyric acid type A (GABAA) receptor, diazepam also binds to etomidate binding sites located in the transmembrane receptor domain. Because such binding is characterized by low modulatory efficacy, the authors hypothesized that diazepam would act in vitro and in vivo as a competitive etomidate antagonist.

Methods: The concentration-dependent actions of diazepam on 20 µM etomidate-activated and 6 µM GABA-activated currents were defined (in the absence and presence of flumazenil) in oocyte-expressed α1β3γ2L GABAA receptors using voltage clamp electrophysiology.

Computational Approaches to Anesthetic Drug Discovery.

All currently available general anesthetics produce potentially deadly side effects. Unfortunately, few approaches have been developed to design safer ones, despite important advances in anesthetic mechanisms research. Cayla and colleagues recently showed that computational methods can be used to identify anesthetic lead compounds devoid of specific side effects.