Biased Mu-Opioid Receptor Analgesics to Prevent Overdose and Opioid Use Disorders

美国约有1亿人遭受痛苦，约900万至1200万人遭受痛苦 从慢性或持续性疼痛1由于阿片类药物仍处于治疗的最前线，阿片类药物滥用已变得明显 阿片类药物过量已成为重大而复杂的公共卫生挑战。阿片类药物过量是 是美国意外死亡的主要原因，估计每天有100人死于阿片类药物过量 2.尽管使用和滥用药物的增加无疑是多种因素造成的 对于阿片类药物，迫切需要一种有效的阿片类止痛剂，以解决围绕 阿片类药物滥用责任和过量死亡。我们对相关药理机制的了解进展 通过G蛋白偶联受体的信号传递，人们已经了解到，Mu阿片受体的激活 (MOR)同时调节治疗和不良反应，并通过药理上不同的信号转导实现 小路。与吗啡和其他吗啡激动剂相关的不良反应已被追踪到通过 β-arrestin途径，而镇痛与G-蛋白途径有关。G蛋白特异性激动剂，可避免激活 β-arrestin信号及其相关的负性后果为通路的发展提供了新的策略 专用于有选择性地产生止痛，同时消除不良反应的特定或有偏向的药物，包括 呼吸抑制、滥用倾向和便秘。 Mebias Discovery LLC已经开发了一种新的平台，并已经确定了有效的高度“偏向”的MOR激动剂 止痛药，但没有阿片类药物引起的不良反应。梅比亚斯的临床前研究比较了两种化合物， MEB-1166和MEB-1170，对特雷维纳的奥利塞定(TRV-130)和吗啡。在4倍的剂量下，达到 其药效相当于吗啡的ED80，两种化合物均未表现出呼吸抑制，而吗啡 奥利克里定显著降低呼吸功能。与吗啡相反，无论是MEB-1166还是MEB-1170 产生了有条件的地点偏好，表明没有滥用责任。 本申请的UG3部分概述的研究是基于到目前为止收集的这些令人鼓舞的结果，并 旨在提供对MEB-1166和MEB-1170的全面评估，以确定其药品和 选择IND研究的候选药物的药理学概况。我们还将进行滥用责任研究和 在更广泛的疼痛模型中检查止痛活性。在完成本建议的UG3部分后，我们 预计MEB-1166或MEB-1170将进入本申请的UH3部分，进行阶段1研究 研究健康志愿者的单次和多次递增剂量研究，以及“Connoisseur研究”中的滥用倾向。 1卡利夫，罗伯特·M，珍妮特·伍德科克和斯蒂芬·奥斯特罗夫，“对处方阿片类药物滥用的积极反应。”新的 《英格兰医学杂志》374，第15期(2016)：1480-1485。 2“阿片类药物过量”疾病控制和预防中心。2017年8月30日。2018年1月12日访问。 Https://www.cdc.gov/drugoverdose/epidemic/index.html

Approximately 100 million people in the United States suffer from pain with some 9 to 12 million individuals suffering from chronic or persistent pain.1 With opioids remaining at the forefront of treatment, it has become clear that opioid abuse and opioid overdose have emerged as significant and complicated public health challenges. Drug overdose from opioids is the leading cause of accidental death in the U.S. with an estimated 100 individuals a day dying from opioid overdose due to respiratory depression.2 Although multiple factors are unquestionably responsible for the increase in the use and abuse of opioids, there is a pressing need for an effective opioid analgesic that also addresses the significant issues surrounding opioid abuse liability and overdose fatalities. Advances in our understanding of the pharmacological mechanisms associated with signaling of G-protein coupled receptors have resulted in the knowledge that activation of the mu-opioid receptor (MOR) mediates both the therapeutic and adverse effects and does so through pharmacologically distinct signaling pathways. The adverse effects associated with morphine and other MOR agonists have been traced to action through the β-arrestin pathway, while analgesia is tied to the G-protein pathway. G-protein specific agonists that avoid activation of β-arrestin signaling and its associated negative consequences provide novel strategies for the development of pathway specific or ‘biased’ drugs designed to selectively produce analgesia while eliminating unwanted adverse effects that include respiratory depression, abuse liability, and constipation. Mebias Discovery LLC has developed a novel platform and has identified highly ‘biased’ MOR agonists that are effective analgesics but are devoid of opioid induced adverse effects. Mebias’ preclinical studies compared two compounds, MEB-1166 and MEB-1170, against Trevena’s Oliceridine (TRV-130) and morphine. At a dose 4X that required to reach the efficacy equivalent to ED80 of morphine, both Mebias compounds displayed no respiratory depression, while morphine and Oliceridine significantly reduced respiratory function. In contrast to morphine, neither MEB-1166 nor MEB-1170 produced conditioned place preference, suggesting an absence of abuse liability. The research outlined in the UG3 portion of this application is based on these encouraging results collected thus far and is designed to provide a thorough evaluation of MEB-1166 and MEB-1170 to characterize their pharmaceutical and pharmacological profiles to select a candidate for IND-enabling studies. We will also conduct abuse liability studies and examine analgesic activity in a wider range of pain models. Upon completion of the UG3 portion of this proposal, we anticipate that MEB-1166 or MEB-1170 will proceed into the UH3 portion of this application conducting Phase 1 studies to examine single and multiple ascending dose studies in healthy volunteers and abuse liability in a ‘Connoisseur study’. 1 Califf, Robert M., Janet Woodcock, and Stephen Ostroff." A proactive response to prescription opioid abuse." New England Journal of Medicine 374, no.15 (2016): 1480-1485. 2 "Opioid overdose." Centers for Disease Control and Prevention. August 30, 2017. Accessed January 12, 2018. https://www.cdc.gov/drugoverdose/epidemic/index.html