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：
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
项目类别：
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

项目摘要

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

在美国，大约有 1 亿人患有疼痛，其中 9 至 1200 万人患有慢性或持续性疼痛。1 由于阿片类药物仍处于治疗的前沿，很明显，阿片类药物滥用和阿片类药物过量已成为重大而复杂的公共卫生挑战。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呼吸抑制的增加阿片类药物，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阿片类药物滥用的责任和过量死亡的药理学机制的理解取得了进展。与 G 蛋白偶联受体信号传导相关的研究已经导致人们认识到 mu-阿片类药物的激活受体（MOR）介导治疗和不良反应，并通过药理学不同的方式实现这一点与吗啡和其他 MOR 激动剂相关的不良反应已被追溯到作用。通过 β-arrestin 途径，而镇痛则与避免 G 蛋白特异性激动剂相关。 β-arrestin 信号的激活及其相关的负面后果为开发提供了新的策略通路特异性或“偏向”药物，旨在选择性地产生镇痛作用，同时消除不需要的副作用其中包括呼吸抑制、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，该药物没有阿片类药物引起的副作用。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、对阿片类药物的耐受性）已上市的 MOR 药物显示出镇痛、镇静、便秘作用。此外，MEB-1170 在滥用方面也显示出前景。责任模型（自我管理、药物歧视、条件位置偏好、戒断）表明它可能是一种作为一种非成瘾性镇痛药，在疼痛管理中取代 Scheduled II 阿片类药物，成为游戏规则的改变者。 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

项目成果

期刊论文数量（2）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Oxycodone: A Current Perspective on Its Pharmacology, Abuse, and Pharmacotherapeutic Developments.

羟考酮：其药理学、滥用和药物治疗发展的最新观点。

DOI：
发表时间：
2023-11
期刊：
影响因子：
21.1
作者：
Barrett, James E;Shekarabi, Aryan;Inan, Saadet
通讯作者：
Inan, Saadet

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：
发表时间：
2020
期刊：
影响因子：
4.8
作者：
Zhang, Lei;Hu, Xian;Yu, Tianzheng;Chen, Ze;Dohl, Jacob;Li, Xiaoxia;Benedek, David M;Fullerton, Carol S;Wynn, Gary;Barrett, James E;Li, Mian;Russell, Dale W;Biomarker team;Ursano, Robert J
通讯作者：
Ursano, Robert J