BACKGROUND Cushing's syndrome is an endocrine disorder characterized by the overproduction of adrenocortical steroids. Steroidogenesis enzyme inhibitors are the mainstays of pharmacological treatment. Unfortunately, they produce significant side effects. Among the most potent inhibitors is the general anesthetic etomidate whose GABAA receptor-mediated sedative-hypnotic actions restrict use. In this study, we defined the sedative-hypnotic and steroidogenesis inhibiting actions of etomidate and four phenyl-ring substituted etomidate analogs (dimethoxy-etomidate, isopropoxy-etomidate, naphthalene-etomidate, and naphthalene (2)-etomidate) that possess negligible GABAA receptor modulatory activities. METHODS In the first set of experiments, male Sprague-Dawley rats were assessed for loss of righting reflexes (LoRR) after receiving intravenous boluses of either etomidate (1 mg/kg) or an etomidate analog (40 mg/kg). In the second set of experiments, rats were assessed for LoRR and their abilities to produce adrenocortical and androgenic steroids after receiving 2-h infusions (0.5 mg kg- 1 min- 1) of either etomidate or an etomidate analog. RESULTS All rats that received etomidate boluses or infusions had LoRR that persisted for minutes or hours, respectively. In contrast, no rat that received an etomidate analog had LoRR. Compared to rats in the vehicle control group, rats that received etomidate analog infusions had plasma corticosterone and aldosterone concentrations that were reduced by 80-84% and 68-94%, respectively. Rats that received etomidate infusions had plasma corticosterone and aldosterone concentrations that were also significantly reduced (by 92 and 96%, respectively). Rats that received etomidate or isopropoxy-etomidate had significant reductions (90 and 57%, respectively) in plasma testosterone concentrations whereas those that received naphthalene-etomidate had significant increases (1400%) in plasma dehydroepiandrosterone concentrations. Neither etomidate nor any etomidate analog significantly affected plasma androstenedione and dihydrotestosterone concentrations. CONCLUSIONS Our studies demonstrate that the four phenyl-ring substituted etomidate analogs form a novel class of compounds that are devoid of sedative-hypnotic activities and suppress plasma concentrations of adrenocortical steroids but vary in their effects on plasma concentrations of androgenic steroids.

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苯环取代的依托咪酯类似物在大鼠中的行为学和甾体生成药理学。

背景技术库欣氏综合症是一种以肾上腺皮质类固醇过量产生为特征的内分泌疾病。类固醇生成酶抑制剂是药物治疗的主要手段。不幸的是，它们产生明显的副作用。最有效的抑制剂之一是全身麻醉的依托咪酯，其GABAA受体介导的镇静催眠作用限制了其使用。在这项研究中，我们定义了依托咪酯和具有可忽略的GABAA受体的四个苯环取代的依托咪酯类似物（二甲氧基-依托咪酯，异丙氧基-依托咪酯，萘-依托咪酯和萘（2）-依托咪酯）的镇静催眠和类固醇抑制作用。调节活动。方法在第一组实验中，在接受静脉内推注依托咪酯（1 mg / kg）或依托咪酯类似物（40 mg / kg）后，对雄性Sprague-Dawley大鼠进行了纠正翻身反射（LoRR）的评估。在第二组实验中，评估大鼠接受依托咪酯或依托咪酯类似物2小时输注（0.5 mg kg-1 min-1）后的LoRR及其产生肾上腺皮质激素和雄激素类固醇的能力。结果所有接受依托咪酯大剂量或输注的大鼠的LoRR分别持续数分钟或数小时。相反，没有任何接受依托咪酯类似物的大鼠具有LoRR。与赋形剂对照组相比，接受依托咪酯类似物输注的大鼠血浆皮质酮和醛固酮浓度分别降低了80-84％和68-94％。接受依托咪酯输注的大鼠血浆皮质酮和醛固酮浓度也显着降低（分别降低了92％和96％）。接受依托咪酯或异丙氧基-依托咪酯的大鼠血浆睾丸激素浓度明显降低（分别为90％和57％），而接受萘-依托咪酯的大鼠血浆脱氢表雄酮浓度明显升高（1400％）。依托咪酯或任何依托咪酯类似物均未显着影响血浆雄烯二酮和二氢睾丸激素的浓度。