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，有9至1200万人患有 慢性或持续性疼痛。1阿片类药物仍然处于治疗的最前沿，很明显阿片类药物滥用和 Opioid过量已成为重大且复杂的公共卫生挑战。药物过量的烯烃是 美国意外死亡的主要原因，估计每天有100人因阿片类药物过量而死亡 呼吸道抑郁症。2尽管多种因素无疑是造成增加和滥用使用和滥用的原因 opioids，迫切需要有效的绿核酸镇痛药，这也解决了周围的重大问题 Oopioid滥用责任和过量死亡。我们对药物机制的理解的进步 与G蛋白偶联受体的信号传导相关的已经导致了以下知识。 受体（MOR）介导治疗和不良反应，并通过药物不同 信号通路。与吗啡和其他MOR激动剂有关的不利影响已被追溯到作用 穿过β-arrestin途径，而镇痛与G蛋白途径相关。 G蛋白特定的激动剂，避免 激活β-arrestin信号及其相关的负面后果为发展提供了新的策略 特定途径或“偏见”药物旨在选择性地产生镇痛，同时消除不良的不良反应 其中包括呼吸抑郁症，虐待责任和便秘。 Mebias Discovery，Inc。开发了一个新颖的平台，并确定了高度“有偏见的”型激动剂，它们是有效的 镇痛药，但没有阿片类药物引起的不良反应。 MEBIAS对其IND候选MEB-1170的临床前研究 在没有已知阿片类药物不良影响的3个疼痛模型中显示出有效性（呼吸抑郁症，容忍度 镇痛，镇静，便秘）由销售的MOR药物显示。此外，MEB-1170显示了滥用的希望 责任模型（自我管理，药物歧视，状况位置偏好，戒断）表明这可能是 游戏规则改变者是一种非添加性镇痛药，以替代疼痛管理中预定的II阿片类药物。 1卡利夫，罗伯特·M。，珍妮特·伍德考克和斯蒂芬·奥斯特罗夫。新的 英格兰医学杂志374，第15号（2016）：1480-1485。 2“阿片类药物过量。”疾病控制与预防中心。 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