Abstract
BackgroundCushing’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.MethodsIn 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.ResultsAll 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.ConclusionsOur 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.
Highlights
Cushing’s syndrome is an endocrine disorder characterized by the overproduction of adrenocortical steroids
We describe studies to further define the pharmacology of this compound along with three additional phenyl ring substituted etomidate analogs that are lacking in significant GABAA receptor modulatory activity (Fig. 2) [24]
Our studies show that these phenyl ring substituted etomidate analogs form a novel class of compounds that retain the ability of etomidate to suppress adrenocortical steroid biosynthesis but do not have sedative-hypnotic activity
Summary
Cushing’s syndrome is an endocrine disorder characterized by the overproduction of adrenocortical steroids. Several classes of drugs can be utilized in the treatment of Cushing’s syndrome, steroidogenesis enzyme inhibitors are the mainstays of pharmacological management [15]. Steroidogenesis inhibitors suppress cortisol production by inhibiting enzymes required for the biosynthesis of adrenocortical steroids (Fig. 1). These enzymes fall into one of two structurally related superfamilies, cytochrome P450s and hydroxysteroid dehydrogenases. The most commonly employed steroidogenesis enzyme inhibitors are ketoconazole and metyrapone, aminoglutethimide, mitotane, and fluconazole are sometimes used [15] All of these drugs have significant adverse side effects that limit dosing, clinical effectiveness, and patient tolerability, and none have been approved by the United States Food and Drug Administration for the treatment of Cushing’s syndrome. There are ongoing efforts to develop new drugs with improved pharmacological profiles [16]
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
