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

美国大约有 1 亿人遭受痛苦，其中约 9 至 1200 万人遭受痛苦 1 由于阿片类药物仍处于治疗的最前沿，很明显，阿片类药物滥用阿片类药物过量已成为重大而复杂的公共卫生挑战。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 尽管毫无疑问多种因素导致了使用和滥用的增加对于阿片类药物，迫切需要一种有效的阿片类镇痛药，同时解决围绕阿片类药物的重大问题我们对相关药理学机制的理解取得了进展。通过 G 蛋白偶联受体的信号传导，我们发现 mu-阿片受体的激活 (MOR) 通过药理学上不同的信号传导介导治疗作用和不良反应与吗啡和其他 MOR 激动剂相关的不良反应可追溯到通过以下途径发挥作用。 β-arrestin 通路，而镇痛则与 G 蛋白通路相关，可避免激活。 β-抑制蛋白信号传导及其相关的负面后果为途径的开发提供了新的策略特定或“有偏见”的药物，旨在选择性地产生镇痛作用，同时避免不必要的副作用，包括呼吸抑制、滥用倾向和便秘。 Mebias Discovery, Inc. 开发了一个新颖的平台，并发现了高度“偏向”的有效 MOR 激动剂 Mebias 对其 IND 候选药物 MEB-1170 进行的临床前研究表明，该药物是镇痛药，但没有阿片类药物引起的不良反应。在 3 种疼痛模型中显示出疗效，且没有已知的阿片类药物副作用（呼吸抑制、镇痛耐受、已上市的 MOR 药物显示出镇静作用、便秘作用。此外，MEB-1170 在滥用倾向模型中显示出前景。（自我管理、药物歧视、条件位置偏好、戒断）表明它可能会改变游戏规则，因为一种非成瘾性镇痛药，用于替代 II 类阿片类药物用于疼痛治疗。补充资金请求将用于帮助支付 MEB-1170 的 GMP 规模扩大的成本计划进行 1 期临床研究。 1 Califf、Robert M.、Janet Woodcock 和 Stephen Ostroff。“对处方阿片类药物滥用的积极反应”。英国医学杂志 374，第 15 期（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