Effects of a G protein-biased mu opioid receptor agonist PZM21 in primates

MU阿片肽(MOP)受体激动剂，如吗啡，是使用最广泛的止痛药 止痛药。然而，MOP受体激动剂相关的滥用易感性和死亡率导致 造成全球社会日益沉重的医疗和经济负担。最近的证据表明 偏向的G蛋白激活的MOP受体激动剂仍有止痛作用，但它们 没有MOP受体介导的副作用。这类化合物还没有被研究过 系统地在具有翻译潜力的非人灵长类(NHP)模型中。在此应用程序中，我们 选择一种新发现的基于G蛋白的MOP受体激动剂PZM21，它将被 张亚南博士在三角研究所合成。一系列的NHP实验将是 PZM21与临床使用拖把的疗效对比研究 急性重复给药后的受体激动剂。这些NHP分析已经被 专门设计以反映治疗(止痛)和副作用(滥用倾向， 呼吸抑制、便秘、身体依赖和阿片类镇痛剂的耐受性)。这个 具有G蛋白偏向激动剂的药物成为副作用减少的有效镇痛剂的可能性 这种作用鼓励了我们在NHP模型中对PZM21的药理研究。我们独特的一套 对清醒、行为正常的恒河猴进行生理和行为分析，结合 一种新的G蛋白偏向MOP受体激动剂PZM21的上市为突破性进展奠定了基础 用于鉴定灵长类动物中安全、非成瘾的镇痛剂，并为未来的临床提供指导 使用新型阿片类止痛药的干预。

Mu opioid peptide (MOP) receptor agonists such as morphine are the most widely used analgesics for pain management. However, MOP receptor agonist-assoicated abuse liability and mortality lead to mounting medical and economic burdens in the global community. Recent evidence indicates that biased MOP receptor agonists with preferred G protein activation retain analgesic effects, but they are devoid of MOP receptor-mediated side effects. Such compounds have not been studied systemically in non-human primate (NHP) models with translational potential. In this application, we select a newly discovered G protein-baised MOP receptor agonist, PZM21, which will be synthesized by Dr. Yanan Zhang at Research Triangle Institute. A series of NHP experiments will be conducted to evaluate effects of PZM21 in side-by-side comparisons with clinically used MOP receptor agonists following acute and repeated administration. These NHP assays have been designed specifically to reflect the therapeutic (analgesia) and side effects (abuse liability, respriatory depression, constipation, physical dependence, and tolerance) of opioid analgesics. The possibility that drugs with G protein-biased agonism will be effective analgesics with reduced side effects encourages our pharmacological studies of PZM21 in NHP models. Our unique set of physiological and behavioral assays in awake, behaving rhesus monkeys, in combination with the availability of a novel G protein-biased MOP receptor agonist PZM21, sets the breakthrough stage for the identification of safe, non-addictive analgesics in primates and sheds light on future clinical interventions with novel opioid analgesics.