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AZD-3043：一种新型代谢不稳定的镇静催眠药，具有快速和可预测的催眠苏醒。

AZD-3043: a novel, metabolically labile sedative-hypnotic agent with rapid and predictable emergence from hypnosis.

机构信息

Department of Anesthesiology, University of Utah School of Medicine, Salt Lake City, UT 84132, USA.

出版信息

Anesthesiology. 2012 Jun;116(6):1267-77. doi: 10.1097/ALN.0b013e31825685a6.

DOI:10.1097/ALN.0b013e31825685a6
PMID:22531340
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC4056591/
Abstract

BACKGROUND

Propofol can be associated with delayed awakening after prolonged infusion. The aim of this study was to characterize the preclinical pharmacology of AZD-3043, a positive allosteric modulator of the γ-aminobutyric acid type A (GABA(A)) receptor containing a metabolically labile ester moiety. The authors postulated that its metabolic pathway would result in a short-acting clinical profile.

METHODS

The effects of AZD-3043, propofol, and propanidid were studied on GABA(A) receptor-mediated chloride currents in embryonic rat cortical neurons. Radioligand binding studies were also performed. The in vitro stability of AZD-3043 in whole blood and liver microsomes was evaluated. The duration of the loss of righting reflex and effects on the electroencephalograph evoked by bolus or infusion intravenous administration were assessed in rats. A mixed-effects kinetic-dynamic model using minipigs permitted exploration of the clinical pharmacology of AZD-3043.

RESULTS

AZD-3043 potentiated GABA(A) receptor-mediated chloride currents and inhibited [(35)S]tert-butylbicyclophosphorothionate binding to GABA(A) receptors. AZD-3043 was rapidly hydrolyzed in liver microsomes from humans and animals. AZD-3043 produced hypnosis and electroencephalograph depression in rats. Compared with propofol, AZD-3043 was shorter acting in rats and pigs. Computer simulation using the porcine kinetic-dynamic model demonstrated that AZD-3043 has very short 50 and 80% decrement times independent of infusion duration.

CONCLUSIONS

AZD-3043 is a positive allosteric modulator of the GABA(A) receptor in vitro and a sedative-hypnotic agent in vivo. The esterase dependent metabolic pathway results in rapid clearance and short duration of action even for long infusions. AZD-3043 may have clinical potential as a sedative-hypnotic agent with rapid and predictable recovery.

摘要

背景

丙泊酚输注时间延长可导致苏醒延迟。本研究旨在研究 AZD-3043 的临床前药理学特性，AZD-3043 是一种 γ-氨基丁酸 A 型（GABA(A)) 受体的正变构调节剂，含有代谢不稳定的酯基。作者推测其代谢途径将产生一种起效迅速的临床特征。

方法

研究了 AZD-3043、丙泊酚和丙泊酚酰胺对胚胎大鼠皮质神经元中 GABA(A) 受体介导的氯离子电流的影响。还进行了放射性配体结合研究。评估了 AZD-3043 在全血和肝微粒体中的体外稳定性。在大鼠中评估了静脉推注或输注时失去翻正反射的持续时间以及对脑电图的影响。使用小型猪的混合效应动力学-动力学模型探索了 AZD-3043 的临床药理学。

结果

AZD-3043 增强了 GABA(A) 受体介导的氯离子电流，并抑制了 [(35)S]叔丁基双环膦酸酯结合到 GABA(A) 受体上。AZD-3043 在人和动物的肝微粒体中迅速水解。AZD-3043 在大鼠中产生催眠和脑电图抑制作用。与丙泊酚相比，AZD-3043 在大鼠和猪中的作用时间更短。使用猪的动力学-动力学模型进行计算机模拟表明，AZD-3043 具有非常短的 50%和 80%衰减时间，与输注持续时间无关。

结论

AZD-3043 是体外 GABA(A) 受体的正变构调节剂，也是体内镇静催眠药。依赖酯酶的代谢途径导致快速清除和作用时间短，即使是长时间输注。AZD-3043 作为一种起效迅速且可预测恢复的镇静催眠药，可能具有临床潜力。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2752/4056591/b0634062ad17/nihms372109f8.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2752/4056591/e20e3eb0e084/nihms372109f5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2752/4056591/544b61ad9388/nihms372109f6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2752/4056591/efd41969a098/nihms372109f7.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2752/4056591/b0634062ad17/nihms372109f8.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2752/4056591/6f0741d42ce2/nihms372109f1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2752/4056591/972f056240b4/nihms372109f2.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2752/4056591/544b61ad9388/nihms372109f6.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2752/4056591/b0634062ad17/nihms372109f8.jpg

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