AZD-3043: a novel, metabolically labile sedative-hypnotic agent with rapid and predictable emergence from hypnosis.
AZD-3043: a novel, metabolically labile sedative-hypnotic agent with rapid and predictable emergence from hypnosis.
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DOI：
10.1097/aln.0b013e31825685a6
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发表时间：
2012-06
期刊：
影响因子：
8.8
通讯作者：
Beattie DT
中科院分区：
文献类型：
--
作者：
Egan TD;Obara S;Jenkins TE;Jaw-Tsai SS;Amagasu S;Cook DR;Steffensen SC;Beattie DT
丙泊酚可能与长时间输注后延迟觉醒有关。本研究的目的是表征AZD-3043的临床前药理学，AZD-3043是一种含有代谢不稳定酯部分的γ-氨基丁酸A（GABAA）受体的正变构调节剂。我们推测其代谢途径将导致短效临床特征。研究了AZD-3043、丙泊酚和丙尼地对胚胎大鼠皮层神经元GABAA受体介导的氯电流的影响。还进行了放射性配体结合研究。评价了AZD-3043在全血和肝微粒体中的体外稳定性。在大鼠中评估翻正反射丧失的持续时间和对推注或静脉（IV）输注给药诱发的脑电图的影响。使用小型猪的混合效应动力学-动力学模型允许探索AZD-3043的临床药理学。AZD-3043增强GABAA受体介导的氯电流，并抑制[35 S]叔丁基双环硫代磷酸酯与GABAA受体的结合。AZD-3043在人和动物肝微粒体中快速水解。AZD-3043对大鼠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。使用猪动力学-动力学模型进行的计算机模拟表明，AZD-3043具有非常短的50%和80%减量时间，与输注持续时间无关。AZD-3043在体外是GABAA受体的正变构调节剂，在体内是镇静/催眠剂。酯酶依赖性代谢途径导致快速清除和短的作用持续时间，即使是长时间输注。AZD-3043可能具有作为镇静/催眠药的临床潜力，具有快速和可预测的恢复。
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 acidA (GABAA) receptor containing a metabolically-labile ester moiety. We postulated that its metabolic pathway would result in a short acting clinical profile. The effects of AZD-3043, propofol and propanidid were studied on GABAA 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 (IV) administration were assessed in rats. A mixed-effects kinetic-dynamic model using minipigs permitted exploration of the clinical pharmacology of AZD-3043. AZD-3043 potentiated GABAA receptor-mediated chloride currents and inhibited [35S]tert-butylbicyclophosphorothionate binding to GABAA receptors. AZD-3043 was rapidly hydrolyzed in liver microsomes from humans and animals. AZD-3043 produced hypnosis and electroencephalograph depression in rats. Compared to 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. AZD-3043 is a positive allosteric modulator of the GABAA 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.