TY - JOUR T1 - <strong>A Novel Etomidate Analogue EL-0052 Retains Potent Hypnotic Effect and Stable Hemodynamics without Suppressing Adrenocortical Function</strong> JF - Journal of Pharmacology and Experimental Therapeutics JO - J Pharmacol Exp Ther DO - 10.1124/jpet.121.000691 SP - JPET-AR-2021-000691 AU - Xiangqing Xu AU - Yaqin Wei AU - Yingying Dong AU - Yinli Qiu AU - Zhanbiao Mei AU - Kai Wang AU - Jingya Xiu AU - Tao Wang AU - Lingguo Zeng AU - Xiaohu Dong AU - Yi Shen AU - Wengao Jiang AU - Qingeng Li Y1 - 2021/01/01 UR - http://jpet.aspetjournals.org/content/early/2021/09/14/jpet.121.000691.abstract N2 - 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 analogue 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 50% of maximal effect (EC50) of 0.98 {plus minus} 0.02 μM, which was about three times more potent than etomidate (3.07 {plus minus} 1.67 μM). Similar to hypnotic potency of etomidate, EL-0052 exhibited loss of righting reflex (LORR) 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, 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 (MAP) 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 a half inhibitory concentration (IC50) of 1050 {plus minus} 100 nM, which was 2.09 {plus minus} 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 analogue EL-0052 retains the favorable properties of etomidate without suppressing adrenocortical function and provides a new strategy to optimize the structure of etomidate. ER -