%0 Journal Article %A Megan McGrath %A Celena Ma %A Douglas Raines %T Dimethoxy-etomidate: A Non-hypnotic Etomidate Analog that Potently Inhibits Steroidogenesis %D 2017 %R 10.1124/jpet.117.245332 %J Journal of Pharmacology and Experimental Therapeutics %P jpet.117.245332 %X 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 for 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 GABAA receptor. Here, we describe the pharmacology of the novel etomidate analog (R)-ethyl 1-(1-(3,5-dimethoxyphenyl)ethyl)-1H-imidazole-5-carboxylate (dimethyoxy-etomidate). In contrast to etomidate, dimethoxy-etomidate minimally enhanced GABA-evoked GABAA 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 two 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’s of 8.2 nM 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 GABAA 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. %U https://jpet.aspetjournals.org/content/jpet/early/2017/12/04/jpet.117.245332.full.pdf