RT Journal Article SR Electronic T1 A Novel Etomidate Analog EL-0052 Retains Potent Hypnotic Effect and Stable Hemodynamics without Suppressing Adrenocortical Function JF Journal of Pharmacology and Experimental Therapeutics JO J Pharmacol Exp Ther FD American Society for Pharmacology and Experimental Therapeutics SP 324 OP 330 DO 10.1124/jpet.121.000691 VO 379 IS 3 A1 Xiangqing Xu A1 Yaqin Wei A1 Yingying Dong A1 Yinli Qiu A1 Zhanbiao Mei A1 Kai Wang A1 Jingya Xiu A1 Tao Wang A1 Lingguo Zeng A1 Xiaohu Dong A1 Yi Shen A1 Wengao Jiang A1 Qingeng Li YR 2021 UL http://jpet.aspetjournals.org/content/379/3/324.abstract AB Etomidate is a potent and rapidly acting anesthetic with high therapeutic index (TI) and superior hemodynamic stability. However, side effect of suppressing adrenocortical function limits its clinical use. To overcome this side effect, we designed a novel etomidate analog, EL-0052, aiming to retain beneficial properties of etomidate and avoid its disadvantage of suppressing adrenocortical steroid synthesis. Results exhibited that EL-0052 enhanced GABAA receptors currents with a concentration for EC50 of 0.98 ± 0.02 μM, which was about three times more potent than etomidate (3.07 ± 1.67 μM). Similar to hypnotic potency of etomidate, EL-0052 exhibited loss of righting reflex with ED50s of 1.02 (0.93–1.20) mg/kg in rats and 0.5 (0.45–0.56) mg/kg in dogs. The TI of EL-0052 in rats was 28, which was higher than 22 of etomidate. There was no significant difference in hypnotic onset time, recovery time, and walking time between EL-0052 and etomidate in rats. Both of them had minor effects on mean arterial pressure in dogs. EL-0052 had no significant effect on adrenocortical function in dogs even at a high dose (4.3 × ED50), whereas etomidate significantly inhibited corticosteroid secretion. The inhibition of cortisol synthesis assay showed that EL-0052 had a weak inhibition on cortisol biosynthesis in human H259 cells with an IC50 of 1050 ± 100 nM, which was 2.09 ± 0.27 nM for etomidate. EL-0052 retains the favorable properties of etomidate, including potent hypnotic effect, rapid onset and recovery, stable hemodynamics, and high therapeutic index without suppression of adrenocortical function.SIGNIFICANCE STATEMENT The novel etomidate analog EL-0052 retains the favorable properties of etomidate without suppressing adrenocortical function and provides a new strategy to optimize the structure of etomidate.