Structure Activity Relationships and Discovery of a G Protein Biased μ Opioid Receptor Ligand, [(3-Methoxythiophen-2-yl)methyl]a2[(9R)-9-(pyridin-2-y1)-6-oxaspiro-[4.5]clecan-9-yl]ethylpamine (TRV130), for the Treatment of Acute Severe Pain
Structure Activity Relationships and Discovery of a G Protein Biased μ Opioid Receptor Ligand, [(3-Methoxythiophen-2-yl)methyl]a2[(9R)-9-(pyridin-2-y1)-6-oxaspiro-[4.5]clecan-9-yl]ethylpamine (TRV130), for the Treatment of Acute Severe Pain
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DOI：
10.1021/jm4010829
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发表时间：
2013-10-24
影响因子：
7.3
通讯作者：
Yamashita, Dennis S.
中科院分区：
文献类型：
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作者：
Chen, Xiao-Tao;Pitis, Philip;Yamashita, Dennis S.
在G蛋白偶联受体上引入了“配体偏向”的概念来描述优先刺激一条细胞内信号通路的配体。人们对开发有偏见的G蛋白偶联受体配体以产生更安全、更好的耐受性和更有效的药物越来越感兴趣。与野生型小鼠相比，经典的Mu阿片类吗啡在fl-arrestin-2基因敲除小鼠中的镇痛效果和持续时间增加，副作用减少，这表明G蛋白偏向的p阿片受体激动剂将更有效，不良事件更少。在这里，我们描述了我们为确定一种有效的、选择性的和G蛋白偏向的p阿片受体激动剂TRV130((R)-30)所做的努力。这种新分子在啮齿动物模型中显示了改善的治疗指数(止痛与不良反应)，并具有适合临床开发的特征。目前正在人体临床试验中对其进行评估，以治疗急性剧烈疼痛。
The concept of "ligand bias" at G protein coupled receptors has been introduced to describe ligands which preferentially stimulate one intracellular signaling pathway over another. There is growing interest in developing biased G protein coupled receptor ligands to yield safer, better tolerated, and more efficacious drugs. The classical mu opioid morphine elicited increased efficacy and duration of analgesic response with reduced side effects in fl-arrestin-2 knockout mice compared to wild-type mice, suggesting that G protein biased p opioid receptor agonists would be more efficacious with reduced adverse events. Here we describe our efforts to identify a potent, selective, and G protein biased p opioid receptor agonist, TRV130 ((R)-30). This novel molecule demonstrated an improved therapeutic index (analgesia vs adverse effects) in rodent models and characteristics appropriate for clinical development. It is currently being evaluated in human clinical trials for the treatment of acute severe pain.