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：
10251374
负责人：
JAMES E. BARRETT
金额：
$ 199.67万
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/10251374
关键词：
Absence of pain sensation Acute Address Adverse effects Adverse event Agonist Analgesics Applications Grants Binding Proteins Biological Assay Biological Availability Brain Canis familiaris Cardiovascular system Centers for Disease Control and Prevention (U.S.)Cessation of life Chronic Clinical Clinical Research Cognitive Constipation Dangerousness Data Development Dose Drug Design Drug Kinetics Epidemic Evaluation Extinction (Psychology)Feeling Female G Protein-Coupled Receptor Signaling GTP-Binding Proteins Generations Human Individual Journals Knowledge Mediating Medicine Metabolism Monitor Morphine Neuropathy New England Nociception Opioid Opioid Analgesics Opioid agonist Oral Overdose Pain Pain Measurement Pathway interactions Penetration Persistent pain Pharmaceutical Preparations Pharmacologic Substance Pharmacology Phase Plasma Proteins Positron-Emission Tomography Pre-Clinical Model Procedures Property Protocols documentation Public Health Rattus Research Respiratory physiology Rodent Route Safety Sedation procedure Self Administration Series Signal Pathway Signal Transduction Solubility Stimulus Surgical incisions Testing Therapeutic Effect Toxic effect Toxicology Translations United States Ventilatory Depression addiction base beta-arrestin carfentanil chronic pain clinical toxicology conditioned place preference design drug candidate drug discrimination experience experimental study gastrointestinal function genotoxicity healthy volunteer in vivo indexing inflammatory pain male meetings mu opioid receptors nonhuman primate novel novel strategies novel therapeutics opioid abuse opioid epidemic opioid overdose opioid use disorder overdose death pain model pain relief phase 1 study pre-clinical preclinical study prescription opioid abuse prevent public health emergency receptor respiratory response safety study scale up screening side effect volunteer

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 LLC 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 compared two compounds, MEB-1166 and MEB-1170, against Trevena’s Oliceridine (TRV-130) and morphine. At a dose 4X that required to reach the efficacy equivalent to ED80 of morphine, both Mebias compounds displayed no respiratory depression, while morphine and Oliceridine significantly reduced respiratory function. In contrast to morphine, neither MEB-1166 nor MEB-1170 produced conditioned place preference, suggesting an absence of abuse liability. The research outlined in the UG3 portion of this application is based on these encouraging results collected thus far and is designed to provide a thorough evaluation of MEB-1166 and MEB-1170 to characterize their pharmaceutical and pharmacological profiles to select a candidate for IND-enabling studies. We will also conduct abuse liability studies and examine analgesic activity in a wider range of pain models. Upon completion of the UG3 portion of this proposal, we anticipate that MEB-1166 or MEB-1170 will proceed into the UH3 portion of this application conducting Phase 1 studies to examine single and multiple ascending dose studies in healthy volunteers and abuse liability in a ‘Connoisseur study’. 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 LLC 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 的临床前研究比较了两种化合物，但没有阿片类药物引起的副作用。 MEB-1166 和 MEB-1170，针对 Trevena 的 Oliceridine (TRV-130) 和吗啡，剂量为达到所需剂量的 4 倍。与吗啡的 ED80 等效，两种 Mebias 化合物均未表现出呼吸抑制，而吗啡与吗啡相比，MEB-1166 和 MEB-1170 均未显着降低呼吸功能。产生了条件性位置偏好，表明不存在滥用倾向。本申请的 UG3 部分中概述的研究基于迄今为止收集的这些令人鼓舞的结果，并且旨在对 MEB-1166 和 MEB-1170 进行全面评估，以表征其药物和性能我们还将进行滥用倾向研究和药理学概况，以选择候选药物进行 IND 研究。在完成该提案的 UG3 部分后，我们检查了更广泛的疼痛模型的镇痛活性。预计 MEB-1166 或 MEB-1170 将进入本申请的 UH3 部分进行第一阶段研究检查健康志愿者的单次和多次递增剂量研究以及“行家研究”中的滥用倾向。 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