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

基本信息

批准号：
10539940
负责人：
JAMES E. BARRETT
金额：
$ 9.5万
依托单位：
MEBIAS DISCOVERY, INC.
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-01-10 至 2022-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10539940
关键词：
Absence of pain sensation Address Adverse effects Agonist Analgesics Applications Grants Centers for Disease Control and Prevention (U.S.)Cessation of life Clinical Research Constipation Dangerousness Development Drug Design Drug Receptors Epidemic Funding G Protein-Coupled Receptor Signaling GTP-Binding Proteins Generations Human Individual Journals Knowledge Mediating Medicine Modeling Morphine New England Opioid Opioid Analgesics Opioid agonist Overdose Pain Pain management Pathway interactions Persistent pain Persons Pharmacology Phase Pre-Clinical Model Public Health Research Schedule 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 cost drug candidate drug discrimination indexing mu opioid receptors novel novel strategies novel therapeutics opioid abuse opioid epidemic opioid overdose opioid use disorder overdose death pain model pain relief preclinical study prescription opioid abuse prevent public health emergency response scale up

项目摘要

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

美国约有1亿人患有疼痛，约9至1200万人受苦从慢性或持续性疼痛中阿片类药物过量已成为重大且复杂的公共卫生挑战。阿片类药物的药物过量是美国意外死亡的主要原因，估计每天100人死于阿片类药物过量呼吸道抑郁症。2尽管毫无疑问，多种因素是使用和滥用的增加在opioids中，需要有效的绿核酸镇痛药，也需要解决周围的重大问题 Oopioid滥用责任和过量死亡。我们对相关药理机制的理解的进步通过G蛋白偶联受体的信号传导，已经知道了Mu-阿片受体的激活（MOR）介导治疗和不良反应，并通过药物不同的信号传导进行途径。与吗啡和其他MOR激动剂相关的不利影响已被追溯到通过 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途径的发展提供了新的策略特定或“偏见”药物旨在有选择性地产生镇痛，同时消除不必要的不良影响，包括呼吸抑郁，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候选人MEB-1170的临床前研究在没有已知阿片类药物不良反应的3个疼痛模型中显示出有效性（呼吸抑制，对镇痛的耐受性，镇静，便秘）由销售的MOR药物显示。此外，MEB-1170显示了虐待责任模型的希望（自我管理，药物歧视，状况位置偏好，撤离）表明它可能是改变游戏规则的人一种非添加性的镇痛药，以替代疼痛管理中预定的II阿片类药物。补充资金请求将用于帮助支付MEB-1170的GMP规模的成本预定的1期临床研究。 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