Biased Opioid Ligands.
Biased Opioid Ligands.
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DOI：
10.3390/molecules25184257
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发表时间：
2020-09-16
期刊：
影响因子：
--
通讯作者：
Majumdar S
中科院分区：
文献类型：
--
作者：
Faouzi A;Varga BR;Majumdar S
实现有效的疼痛管理是现代医学面临的主要挑战之一。阿片类药物，如吗啡，一直是中到重度急性疼痛的参考治疗，不排除慢性疼痛。阿片类药物通过阿片受体发挥作用，阿片受体是G蛋白偶联受体(GPCRs)家族，通过中枢和外周神经系统介导疼痛缓解。目前已有四种类型的阿片受体，包括μ-阿片受体(MOR)、κ-阿片受体(KOR)、δ-阿片受体(DOR)和伤害素阿片肽受体(NOP受体)。尽管阿片类药物在治疗疼痛方面已被证明是成功的，但仍然存在一些固有的局限性。所有临床批准的MOR止痛药都与不良反应有关，包括耐受性、依赖性、成瘾、便秘和呼吸抑制。另一方面，KOR选择性镇痛剂的临床应用有限，因为它们会导致镇静、焦虑、烦躁不安和幻觉。DOR激动剂也被研究过，但它们有引起抽搐的趋势。临床前文献报道，靶向NOP受体的配体可用作脊髓止痛剂和抗物质滥用障碍的实体，而混合的MOR/NOP受体激动剂可用作止痛剂。归根结底，与阿片类药物相关的药物开发的目标一直是设计和合成与吗啡同等或更强的衍生物，但最重要的是没有危险的残留副作用和滥用潜力。一种建议的策略是利用偏向激动法，即不同的下游通路可以被通过完全相同的受体工作的不同分子激活。有人提出，不招募β-arrestin 2或表现出偏好激活特定G蛋白介导的信号转导途径的配体将在所有阿片亚型中发挥更安全的止痛药作用。这篇综述将集中在阿片受体上偏向配体的设计和药理学结果，旨在实现功能选择性。
Achieving effective pain management is one of the major challenges associated with modern day medicine. Opioids, such as morphine, have been the reference treatment for moderate to severe acute pain not excluding chronic pain modalities. Opioids act through the opioid receptors, the family of G-protein coupled receptors (GPCRs) that mediate pain relief through both the central and peripheral nervous systems. Four types of opioid receptors have been described, including the μ-opioid receptor (MOR), κ-opioid receptor (KOR), δ-opioid receptor (DOR), and the nociceptin opioid peptide receptor (NOP receptor). Despite the proven success of opioids in treating pain, there are still some inherent limitations. All clinically approved MOR analgesics are associated with adverse effects, which include tolerance, dependence, addiction, constipation, and respiratory depression. On the other hand, KOR selective analgesics have found limited clinical utility because they cause sedation, anxiety, dysphoria, and hallucinations. DOR agonists have also been investigated but they have a tendency to cause convulsions. Ligands targeting NOP receptor have been reported in the preclinical literature to be useful as spinal analgesics and as entities against substance abuse disorders while mixed MOR/NOP receptor agonists are useful as analgesics. Ultimately, the goal of opioid-related drug development has always been to design and synthesize derivatives that are equally or more potent than morphine but most importantly are devoid of the dangerous residual side effects and abuse potential. One proposed strategy is to take advantage of biased agonism, in which distinct downstream pathways can be activated by different molecules working through the exact same receptor. It has been proposed that ligands not recruiting β-arrestin 2 or showing a preference for activating a specific G-protein mediated signal transduction pathway will function as safer analgesic across all opioid subtypes. This review will focus on the design and the pharmacological outcomes of biased ligands at the opioid receptors, aiming at achieving functional selectivity.
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DOI：
10.1124/jpet.108.146969
发表时间：
2009-04-01
影响因子：
3.5
作者：
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影响因子：
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