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

偏向 Mu-阿片受体镇痛药可预防过量和阿片类药物使用障碍

• 批准号: 10251374
• 负责人: JAMES E. BARRETT
• 金额: $ 199.67万
• 依托单位: MEBIAS DISCOVERY, INC.
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-15 至 2023-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10251374
• 关键词: Absence of pain sensation; Acute; Address; Adverse effects; Adverse event; Agonist; Analgesics; Applications Grants; Binding Proteins; Biological Assay; Biological Availability; Brain; Canis familiaris; Cardiovascular system; Centers for Disease Control and Prevention (U.S.); Cessation of life; Chronic; Clinical; Clinical Research; Cognitive; Constipation; Dangerousness; Data; Development; Dose; Drug Design; Drug Kinetics; Epidemic; Evaluation; Extinction (Psychology); Feeling; Female; G Protein-Coupled Receptor Signaling; GTP-Binding Proteins; Generations; Human; Individual; Journals; Knowledge; Mediating; Medicine; Metabolism; Monitor; Morphine; Neuropathy; New England; Nociception; Opioid; Opioid Analgesics; Opioid agonist; Oral; Overdose; Pain; Pain Measurement; Pathway interactions; Penetration; Persistent pain; Pharmaceutical Preparations; Pharmacologic Substance; Pharmacology; Phase; Plasma Proteins; Positron-Emission Tomography; Pre-Clinical Model; Procedures; Property; Protocols documentation; Public Health; Rattus; Research; Respiratory physiology; Rodent; Route; Safety; Sedation procedure; Self Administration; Series; Signal Pathway; Signal Transduction; Solubility; Stimulus; Surgical incisions; Testing; Therapeutic Effect; Toxic effect; Toxicology; Translations; United States; Ventilatory Depression; addiction; base; beta-arrestin; carfentanil; chronic pain; clinical toxicology; conditioned place preference; design; drug candidate; drug discrimination; experience; experimental study; gastrointestinal function; genotoxicity; healthy volunteer; in vivo; indexing; inflammatory pain; male; meetings; mu opioid receptors; nonhuman primate; novel; novel strategies; novel therapeutics; opioid abuse; opioid epidemic; opioid overdose; opioid use disorder; overdose death; pain model; pain relief; phase 1 study; pre-clinical; preclinical study; prescription opioid abuse; prevent; public health emergency; receptor; respiratory; response; safety study; scale up; screening; side effect; volunteer

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

美国约有1亿人患有疼痛，其中约900万至1200万人患有 1由于阿片类药物仍处于治疗的最前沿，很明显，阿片类药物滥用 和阿片类药物过量已经成为重大和复杂的公共卫生挑战。阿片类药物过量是 这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虽然多种因素无疑是使用和滥用 阿片类药物，迫切需要一种有效的阿片类镇痛药，也解决了周围的重大问题， 阿片类药物滥用和过量死亡。我们对相关药理学机制的理解进展 与G蛋白偶联受体的信号传导的关系已经导致了μ阿片受体的激活 (MOR)介导治疗和副作用，并通过不同的信号传导 途径。与吗啡和其它莫尔激动剂相关的副作用已通过以下途径追溯到作用： β-抑制蛋白途径，而镇痛与G-蛋白途径有关。G蛋白特异性激动剂，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 特定的或“偏向”的药物，旨在选择性地产生镇痛作用，同时消除不必要的副作用，包括 呼吸抑制滥用倾向和便秘 Mebias Discovery LLC开发了一种新的平台，并确定了有效的高度“偏倚”的莫尔激动剂 镇痛剂，但没有阿片样物质诱导的副作用。Mebias的临床前研究比较了两种化合物， MEB-1166和MEB-1170，对抗Trevena's Oliceridine（TRV-130）和吗啡。剂量是达到所需剂量的4倍 与吗啡的ED 80相当的效力，两种Mebias化合物均未显示呼吸抑制，而吗啡 和奥利色定显著降低呼吸功能。与吗啡相比，MEB-1166和MEB-1170均不 产生了条件性的位置偏好，这表明没有滥用责任。 本申请的UG 3部分概述的研究基于迄今为止收集的这些令人鼓舞的结果， 旨在对MEB-1166和MEB-1170进行彻底评估，以表征其药物和 药理学特征，以选择IND使能研究的候选者。我们亦会进行滥用法律责任研究， 在更广泛的疼痛模型中检查镇痛活性。在完成本提案的UG 3部分后，我们 预计MEB-1166或MEB-1170将进入本申请的UH 3部分进行1期研究 检查健康志愿者中的单次和多次递增剂量研究以及“鉴赏家研究”中的滥用倾向。 1 Califf，Robert M.，珍妮特·伍德考克和斯蒂芬·奥斯特罗夫“对处方阿片类药物滥用的积极反应。“新建 England Journal of Medicine 374，no.15（2016）：1480-1485. 2“鸦片过量。“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