更新于：2024-11-01

CYP11B1 x GABAA receptor

更新于：2024-11-01

基本信息

关联

项与 CYP11B1 x GABAA receptor 相关的药物

Metyrapone/Oxazepam

美替拉酮/奥沙西泮

靶点

CYP11B1 x GABAA receptor

作用机制

CYP11B1抑制剂 [+1]

在研机构-

原研机构

Louisiana State University

在研适应症-

非在研适应症

可卡因相关疾病 [+2]

最高研发阶段无进展

首次获批国家/地区-

首次获批日期1800-01-20

项与 CYP11B1 x GABAA receptor 相关的临床试验

NCT04933916 / Terminated临床1/2期

Efficacy and Safety of Combination EMB-001 as a Potential Smoking Cessation Treatment

EMB-001 is a combination of 2 drugs: the cortisol synthesis inhibitor, metyrapone (Metopirone®), and the benzodiazepine receptor agonist, oxazepam (original trade name Serax®; now marketed as oxazepam (generic) only).
This is an open-label study in up to 50 adult subjects to help smokers abstain from smoking during a 12-week trial period.

开始日期2021-06-10

申办/合作机构

Embera NeuroTherapeutics, Inc.

[+2]

NCT04868253 / Unknown status临床2/3期

Efficacy and Safety of Combination EMB-001 as a Potential Smoking Cessation Treatment

This open-label study will evaluate EMB-001, comprised of metyrapone, a cortisol synthesis inhibitor marketed as a diagnostic drug for testing hypothalamic-pituitary-adrenal (HPA) axis function, combined with oxazepam, an anxiolytic and sedative/hypnotic benzodiazepine, to help smokers abstain from smoking during a 12-week trial period.

开始日期2021-05-19

申办/合作机构

Rose Research Center LLC初创企业

[+1]

NCT04501874 / Completed临床2期

A Phase 2, Randomized, Double-Blind, Placebo-Controlled, Parallel Group, Study to Evaluate the Safety and Efficacy of EMB 001 in Subjects With Moderate-to-Severe Cocaine Use Disorder

EMB-001 is a combination of 2 drugs: the cortisol synthesis inhibitor, metyrapone (Metopirone®), and the benzodiazepine receptor agonist, oxazepam (original trade name Serax®; now marketed as oxazepam (generic) only).
This is a Phase 2 study in approximately 80 adult subjects with moderate-to-severe Cocaine Use Disorder (CUD).

开始日期2020-07-29

申办/合作机构

Embera NeuroTherapeutics, Inc.

[+1]

100 项与 CYP11B1 x GABAA receptor 相关的临床结果

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100 项与 CYP11B1 x GABAA receptor 相关的转化医学

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0 项与 CYP11B1 x GABAA receptor 相关的专利（医药）

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项与 CYP11B1 x GABAA receptor 相关的文献（医药）

2018-02-01·Journal of Pharmacology and Experimental Therapeutics3区 · 医学

Dimethoxy-etomidate: A Nonhypnotic Etomidate Analog that Potently Inhibits Steroidogenesis

3区 · 医学

Article

作者: Ma, Celena ; Raines, Douglas E ; McGrath, Megan

Cushing's syndrome is characterized by the overproduction of adrenocortical steroids. Steroidogenesis inhibitors are mainstays of medical therapy for Cushing's syndrome; unfortunately, adverse side effects and treatment failures are common with currently available drugs. The general anesthetic induction agent etomidate is among the most potent inhibitors of adrenocortical steroidogenesis. However, its use as a treatment of Cushing's syndrome is complicated by its sedative-hypnotic activity and ability to produce myoclonus, central nervous system actions thought to be mediated by the GABA_A receptor. Here, we describe the pharmacology of the novel etomidate analog (R)-ethyl 1-(1-(3,5-dimethoxyphenyl)ethyl)-1H-imidazole-5-carboxylate (dimethoxy-etomidate). In contrast to etomidate, dimethoxy-etomidate minimally enhanced GABA-evoked GABA_A receptor-mediated currents even at a near-saturating aqueous concentration. In Sprague-Dawley rats, dimethoxy-etomidate's potency for producing loss of righting reflexes-an animal model of sedation/hypnosis-was 2 orders of magnitude lower than that of etomidate, and it did not produce myoclonus. However, similar to etomidate, dimethoxy-etomidate potently suppressed adrenocortical steroid synthesis primarily by inhibiting 11β-hydroxylase. [³H]etomidate binding to rat adrenocortical membranes was inhibited by dimethoxy-etomidate in a biphasic manner with IC₅₀ values of 8.2 and 3970 nM, whereas that by etomidate was monophasic with an IC₅₀ of 22 nM. Our results demonstrate that, similar to etomidate, dimethoxy-etomidate potently and dose-dependently suppresses adrenocortical steroid synthesis by inhibiting 11β-hydroxylase. However, it is essentially devoid of etomidate's GABA_A receptor positive modulatory and sedative-hypnotic activities and produces no myoclonus, providing proof of concept for the design of etomidate analogs without important central nervous system actions for the pharmacologic treatment of Cushing's syndrome.

2013-02-01·Journal of Cardiothoracic and Vascular Anesthesia4区 · 医学

Con: Etomidate—The Ideal Induction Agent for a Cardiac Anesthetic?

4区 · 医学

Review

作者: Malhotra, Anita K

N IDEAL INDUCTION AGENT would be one that has rapid on- and offset, is easy to administer, and is devoid of clinically significant side effects. Such an agent does not exist currently. Drawbacks to currently available induction agents include the high incidence of hypotension and pain on injection with propofol; dysphoria, tachycardia, hallucinations, and increased secretions with ketamine; hypotension, and an increased incidence of laryngospasm with barbiturates. Etomidate often is the favored induction agent for patients who are hemodynamically compromised because of its relative cardiovascular stability. However, there is ongoing debate about its usage in critically ill patients because of its inhibition of adrenal steroidogenesis.1-8 Unlike propofol, barbiturates, and ketamine, etomidate has a very high therapeutic index. Unique among the general anesthetic induction drugs, the chemical structure of etomidate includes an imidazole ring that is critical for its anesthetic actions, which are mediated by specific -aminobutyric acid type-A receptors in the central nervous system. 9 Regarding its hemodynamic stability, there are minimal effects on blood pressure and heart rate when a single bolus injection is given, even in patients who are in shock or who exhibit depressed left ventricular function. 10 Because of this stability, it often is the agent of choice in the emergency room and the intensive care unit for rapid-sequence inductions and the induction of general anesthesia in the cardiac surgical operating room. However, as early as 1983, reports of adrenal suppression from etomidate injection began to surface. 11,12 The mechanism of adrenal insufficiency is by the inhibition of 11--hydroxylase, the enzyme responsible for the conversion of 11-deoxycortisol to cortisol and 11-deoxycorticosterone to corticosterone.

2003-10-01·European Journal of Nuclear Medicine and Molecular Imaging1区 · 医学

In vivo and in vitro evaluation of [ 18 F]FETO with respect to the adrenocortical and GABAergic system in rats

1区 · 医学

Article

作者: Werner Sieghart ; Markus Mitterhauser ; Helmut Viernstein ; Wolfgang Wadsak ; Robert Dudczak ; Leila Wabnegger ; Kurt Kletter

11beta-Hydroxylase (CYP11B1, P45011beta) plays an important role in the biosynthesis of cortisol and aldosterone and has been shown to be a good target for the in vivo imaging of adrenocortical incidentalomas in nuclear medicine. [11C]Metomidate (MTO), a potent inhibitor of this enzyme, is used for positron emission tomography (PET) imaging of adrenocortical pathology. The synthesis of (R)-1-(1-phenylethyl)-1H-imidazole-5-carboxylic acid 2-[18F]fluoroethylester (FETO), a close analogue to MTO and etomidate (ETO), has been presented recently, and the present investigation aimed to characterise the in vivo distribution of FETO. Since ETO is a well-known anaesthetic drug acting via the GABAergic system, the interaction of FETO with GABAA receptors was also evaluated. Eighteen male Sprague-Dawley rats were injected with 1.73-3.06 MBq of FETO into a tail vein after venodilatation in a 40 degrees C water bath. Rats were sacrificed by exsanguination from the abdominal aorta under deep ether anaesthesia after 10 (n=6), 30 (n=6) or 60 min (n=6); organs were removed, weighed and counted. For binding experiments, rat cerebellar membranes were incubated for 90 min at 4 degrees C in TC-50 buffer, 150 mM NaCl and 2 nM of [3H]flunitrazepam in the absence or presence of 10 microM diazepam or various concentrations of ETO, MTO and FETO. In vivo evaluation evinced very high uptake in the adrenal glands (7.52%+/-1.19% ID/g at 30 min), followed by lung (1.18%+/-0.19% ID/g, 10 min), liver (0.59%+/-0.13% ID/g, 10 min) and duodenum (0.7%+/-0.29% ID/g, 60 min). No defluorination nor fluoroethyl-ester cleavage was observed. When brain regions were compared with the thalamus (the reference region), highest relative uptake was seen in the cortex (2.34), followed by "rest brain" (2.13) and cerebellum (1.96). FETO and ETO were able to increase the binding of [3H]flunitrazepam with similar potencies and to a comparable extent. It is concluded that FETO shows characteristics suitable for the imaging of adrenocortical pathology with PET. Binding experiments on GABA receptors demonstrate a comparable effect of FETO and ETO. Hence, FETO possibly could also be used to elucidate the function, dynamics and kinetics of narcotic drugs with PET.