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: 10749222
• 负责人: JAMES E. BARRETT
• 金额: $ 11万
• 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/10749222
• 关键词: Absence of pain sensation; Accidents; Address; Adverse effects; Agonist; Analgesics; Applications Grants; Centers for Disease Control and Prevention (U.S.); Cessation of life; Constipation; Dangerousness; Development; Drug Design; Drug Receptors; Epidemic; G Protein-Coupled Receptor Signaling; GTP-Binding Proteins; Generations; Individual; Investigational Drugs; Journals; Knowledge; Marketing; Mediating; Medicine; Modeling; Morphine; New England; Opioid; Opioid Analgesics; Opioid agonist; Overdose; Pain; Pain management; Pathway interactions; Persistent pain; Persons; Phase I Clinical Trials; Pre-Clinical Model; Prevention; Public Health; Research; Schedule II opioids; Sedation procedure; Self Administration; Signal Pathway; Signal Transduction; Therapeutic Effect; United States; Ventilatory Depression; Withdrawal; abuse liability; beta-arrestin; chronic pain; conditioned place preference; drug candidate; drug discrimination; indexing; mu opioid receptors; news; novel; novel strategies; novel therapeutics; opioid abuse; opioid epidemic; opioid overdose; opioid use disorder; overdose death; pain model; pain relief; pharmacologic; preclinical study; prescription opioid abuse; prevent; public health emergency; response

Approximately 100 million people in the United States suffer from pain with 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. 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 阿片类药物过量已成为重大和复杂的公共卫生挑战。阿片类药物过量是 阿片类药物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造成使用和滥用麻醉品的增加的原因， 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， 阿片类药物滥用责任和过量死亡。药理机制的研究进展 与G蛋白偶联受体信号传导相关的研究已经导致了μ-阿片样物质的激活 受体（莫尔）介导治疗和副作用，并通过不同的途径介导 信号通路与吗啡和其他莫尔激动剂相关的副作用已被追溯到作用 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， β-arrestin信号的激活及其相关的负面后果为开发 途径特异性或“偏向性”药物，旨在选择性产生镇痛作用，同时消除不必要的副作用 包括呼吸抑制虐待倾向和便秘 Mebias Discovery，Inc.已经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IND候选药物MEB-1170的临床前研究 在3种疼痛模型中显示出疗效，而没有已知的阿片类药物副作用（呼吸抑制、对 镇痛、镇静、便秘）。此外，MEB-1170在滥用方面表现出希望 责任模型（自我管理，药物歧视，条件位置偏好，撤回）表明它可能是一个 游戏规则改变者作为非成瘾性镇痛药，以取代计划II阿片类药物的疼痛管理。 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

项目成果

Genetic association of FKBP5 with PTSD in US service members deployed to Iraq and Afghanistan.

部署到伊拉克和阿富汗的美国军人中 FKBP5 与 PTSD 的基因关联。

• DOI: 10.1016/j.jpsychires.2019.12.014
• 发表时间: 2020
• 期刊: Journal of psychiatric research
• 影响因子: 4.8
• 作者: Zhang,Lei;Hu,Xian-Zhang;Yu,Tianzheng;Chen,Ze;Dohl,Jacob;Li,Xiaoxia;Benedek,DavidM;Fullerton,CarolS;Wynn,Gary;Barrett,JamesE;Li,Mian;Russell,DaleW;Biomarkerteam;Ursano,RobertJ
• 通讯作者: Ursano,RobertJ