Department of Medicinal Chemistry, China Pharmaceutical University, Nanjing 210009, China.
Jiangsu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing 210009, China.
Mini Rev Med Chem. 2018;18(19):1603-1610. doi: 10.2174/1389557518666180716124336.
Opioid analgesics, such as morphine, are widely employed in the treatment of moderate to severe pain. However, they are notorious for abuse liability and respiratory depression. Therefore circumventing the side effects, such as euphoria, addiction, respiratory depression and gastrointestinal adverse reactions, is of extensive importance. Recently, a large number of research results have revealed that such morphine-like side effects are not inevitable, and they focus on the novel approaches to disconnecting the analgesics from adverse effects. In this review, we mainly discuss the approaches including biasing the GPCRs over β-arrestin2 recruitment (TRV130, PZM21, HS665), the positive allosteric modulators of the MOR (BMS-986122) and multiple agonists of opioid receptors subtypes (SNC80, DPI-125). Besides these, we also introduce the key protein sites of MOR and β-arrestin2 recruitment briefly.
阿片类镇痛药，如吗啡，广泛用于治疗中重度疼痛。然而，它们因滥用倾向和呼吸抑制而声名狼藉。因此，规避欣快感、成瘾、呼吸抑制和胃肠道不良反应等副作用具有重要意义。最近，大量研究结果表明，这种类似吗啡的副作用并非不可避免，它们专注于分离镇痛药和副作用的新方法。在这篇综述中，我们主要讨论了几种方法，包括偏向 GPCR 与β-arrestin2 募集（TRV130、PZM21、HS665）、MOR 的正变构调节剂（BMS-986122）和多种阿片受体亚型的激动剂（SNC80、DPI-125）。除此之外，我们还简要介绍了 MOR 和β-arrestin2 募集的关键蛋白位点。
