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，Inc.开发了一种新的平台，并发现了有效的高度“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。MEBIAS对其IND候选药物MEB-1170的临床前研究 在3种疼痛模型中显示了有效性，但没有已知的阿片类药物不良反应(呼吸抑制、镇痛耐受性、 镇静、便秘)由市场上的MOR药物显示。此外，MEB-1170在滥用责任模型方面表现出了希望 (自我管理，药物歧视，条件地点偏好，戒烟)表明这可能是游戏规则的改变者，因为 一种非成瘾性止痛药，用于取代疼痛治疗中预定的II类阿片类药物。 补充资金申请将被用来帮助支付扩大MEB-1170 GMP的成本 预定的第一阶段临床研究。 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, Inc. 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 of its IND candidate MEB-1170 has shown efficacy in 3 pain models without the known opioid adverse effects (respiratory depression, tolerance to analgesia, sedation, constipation) shown by marketed MOR drugs. In addition, MEB-1170 shows promise in abuse liability models (self-administration, drug discrimination, condition place preference, withdrawal) suggesting it could be a game changer as a non-addictive analgesic to replace Scheduled II opioids in pain management. The Supplemental Funding request will be utilized to help cover the cost of the GMP scale up of MEB-1170 for the scheduled Phase 1 clinical studies. 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