A Novel Etomidate Analog EL-0052 Retains Potent Hypnotic Effect and Stable Hemodynamics without Suppressing Adrenocortical Function
A Novel Etomidate Analog EL-0052 Retains Potent Hypnotic Effect and Stable Hemodynamics without Suppressing Adrenocortical Function
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DOI：
10.1124/jpet.121.000691
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发表时间：
2021-12-01
影响因子：
3.5
通讯作者：
Li, Qingeng
中科院分区：
文献类型：
--
作者：
Xu, Xiangqing;Wei, Yaqin;Li, Qingeng
依托咪酯是一种强效、快速起效的麻醉剂，具有高治疗指数 (TI) 和卓越的血流动力学稳定性。但抑制肾上腺皮质功能的副作用限制了其临床应用。为了克服这种副作用，我们设计了一种新型依托咪酯类似物EL-0052，旨在保留依托咪酯的有益特性并避免其抑制肾上腺皮质类固醇合成的缺点。结果显示，EL-0052 增强 GABA(A) 受体电流，EC50 浓度为 0.98 +/- 0.02 muM，其效力大约是依托咪酯 (3.07 +/- 1.67 mM) 的三倍。与依托咪酯的催眠效力相似，EL-0052表现出翻正反射丧失，大鼠中的ED(50)s为1.02(0.93-1.20)mg/kg，狗中的ED(50)s为0.5(0.45-0.56)mg/kg。 EL-0052在大鼠中的TI为28，高于依托咪酯的22。 EL-0052与依托咪酯对大鼠的催眠起效时间、苏醒时间和行走时间无显着差异。它们对狗的平均动脉压都有轻微影响。即使在高剂量（4.3 x ED50）下，EL-0052 对狗的肾上腺皮质功能也没有显着影响，而依托咪酯则显着抑制皮质类固醇的分泌。皮质醇合成抑制试验表明，EL-0052对人H259细胞的皮质醇生物合成有弱抑制作用，IC50为1050+/-100μM，依托咪酯为2.09+/-0.27μM。 EL-0052保留了依托咪酯的有利特性，包括强效催眠作用、快速起效和恢复、稳定的血流动力学以及高治疗指数且不抑制肾上腺皮质功能。 意义说明新型依托咪酯类似物EL-0052保留了依托咪酯的有利特性而不抑制肾上腺皮质功能，并为优化依托咪酯结构提供了新策略。
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 GABA(A) receptors currents with a concentration for EC50 of 0.98 +/- 0.02 mu M, which was about three times more potent than etomidate (3.07 +/- 1.67 mM). Similar to hypnotic potency of etomidate, EL-0052 exhibited loss of righting reflex with ED(50)s 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 x 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 mu M, which was 2.09 +/- 0.27 mu M 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 STATEMENTThe 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.