Nociceptin/Orphanin FQ Peptide Receptor-Related Ligands as Novel Analgesics.
Nociceptin/Orphanin FQ Peptide Receptor-Related Ligands as Novel Analgesics.
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DOI：
10.2174/1568026620666200508082615
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发表时间：
2020
影响因子：
3.4
通讯作者：
Ko MC
中科院分区：
文献类型：
--
作者：
Kiguchi N;Ding H;Kishioka S;Ko MC
尽管在伤害肽/孤啡肽FQ肽（NOP）受体和其他阿片受体中观察到相似的分布模式和细胞内事件，但NOP受体的激活显示出独特的药理学特征。一些研究人员已经确定了多种肽和非肽配体来确定NOP受体激活的功能作用，并观察到NOP受体相关配体表现出疼痛模式依赖性疼痛加工。重要的是，在非人灵长类动物（NHPs）中，无论实验环境如何，NOP受体激活都能在脊柱和脊柱上水平产生抗伤害性和抗超敏反应。鉴于NOP受体激动剂协同增强了mu-阿片肽（MOP）受体激动剂诱导的抗伤害性，我们假设NOP和MOP受体激动剂可能作为镇痛药具有很好的功能特性。越来越多的证据表明，混合NOP/阿片受体激动剂具有良好的功能特征。在NHP研究中，双功能NOP/MOP部分激动剂（如AT-121、BU08028和BU10038）通过NOP和MOP受体激活发挥了有效的抗伤害感受作用；然而，没有观察到与MOP受体激活相关的剂量限制性不良反应，包括呼吸抑制、瘙痒感、身体依赖和滥用倾向。此外，混合NOP/阿片受体激动剂cebranopadol作为一种新型镇痛药在临床试验中表现出良好的效果。总的来说，对NOP和MOP受体的双重激动作用，具有适当的结合亲和力和疗效，可能是开发创新和安全镇痛药的可行策略。
Despite similar distribution patterns and intracellular events observed in the nociceptin/orphanin FQ peptide (NOP) receptor and other opioid receptors, NOP receptor activation displays unique pharmacological profiles. Several researchers have identified a variety of peptide and non-peptide ligands to determine the functional roles of NOP receptor activation and observed that NOP receptor-related ligands exhibit pain modality-dependent pain processing. Importantly, NOP receptor activation results in anti-nociception and anti-hypersensitivity at the spinal and supraspinal levels regardless of the experimental settings in non-human primates (NHPs). Given that the NOP receptor agonists synergistically enhance mu-opioid peptide (MOP) receptor agonist-induced anti-nociception, it has been hypothesized that dual NOP and MOP receptor agonists may display promising functional properties as analgesics. Accumulating evidence indicates that the mixed NOP/opioid receptor agonists demonstrate favorable functional profiles. In NHP studies, bifunctional NOP/MOP partial agonists (e.g., AT-121, BU08028, and BU10038) exerted potent anti-nociception via NOP and MOP receptor activation; however, dose-limiting adverse effects associated with the MOP receptor activation, including respiratory depression, itch sensation, physical dependence, and abuse liability, were not observed. Moreover, a mixed NOP/opioid receptor agonist, cebranopadol, presented promising outcomes in clinical trials as a novel analgesic. Collectively, the dual agonistic actions on NOP and MOP receptors, with appropriate binding affinities and efficacies, may be a viable strategy to develop innovative and safe analgesics.
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影响因子：
3.3
作者：
Berthele, A;Platzer, S;Tölle, TR
通讯作者：
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影响因子：
3.5
作者：
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通讯作者：
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作者：
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通讯作者：
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影响因子：
7.3
作者：
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通讯作者：
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