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：
10223026
负责人：
JAMES E. BARRETT
金额：
$ 314.7万
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/10223026
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 Cessation of life Chronic Clinical Clinical Research Cognitive Constipation Dangerousness Data Development Dose Drug Design Drug Kinetics Evaluation Extinction (Psychology)Feeling Female G Protein-Coupled Receptor Signaling GTP-Binding Proteins Generations Human Individual Knowledge Mediating Medicine Metabolism Monitor Morphine Neuropathy 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 inflammatory pain male meetings mu opioid receptors nonhuman primate novel novel strategies novel therapeutics opioid abuse opioid epidemic opioid overdose opioid use disorder pain model pain relief phase 1 study pre-clinical preclinical study 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. 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. 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’.

在美国，大约有1亿人患有疼痛，大约9至1200万人患有慢性或持续性疼痛。由于阿片类药物仍然处于治疗的最前沿，因此很明显，阿片类药物滥用和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，据估计有100个个体A，尽管多个因素无疑是造成阿片类药物使用和滥用的增加和滥用的原因，但迫切需要有效的阿片类镇痛药，这也解决了围绕阿片类药物滥用责任的重大问题，并解决了过量的死亡。我们对与G蛋白偶联受体信号相关的药理机制的理解的进步已经导致了这样一种知识，即激活Mu-Apoid接收器（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激动剂相关的不良反应已被追溯到通过β-arrestin途径作用，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信号传导及其相关的负面后果为开发途径特定或“有偏见的”药物的开发提供了新的策略，旨在有选择性地产生镇痛，同时消除不需要的广告作用，包括呼吸抑郁，滥用责任和便秘。 Mebias Discovery LLC已经开发了一个新颖的平台，并确定了有效的镇痛药，但缺乏阿片类药物引起的不良影响。 MEBIAS的临床前研究将两种化合物MEB-1166和MEB-1170与Trevena的橄榄石（TRV-130）和吗啡进行了比较。在达到吗啡ED80的有效性所需的4X剂量下，两种MEBIAS化合物均未表现出呼吸抑郁症，而吗啡和橄榄碱显着降低了呼吸功能。与吗啡相反，MEB-1166和MEB-1170均未产生条件的地点偏好，这表明缺乏虐待责任。该应用程序的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，旨在对MEB-1166和MEB-1170进行彻底评估，以表征其药物和药理特征，以选择辅助研究的候选者。我们还将在广泛的疼痛模型中进行滥用责任研究和检查镇痛活性。该提案的UG3部分完成后，我们预计MEB-1166或MEB-1170将继续进行该申请的UH3部分进行第1阶段研究，以检查健康志愿者中的单次和多个升级剂量研究，并滥用“ Connoisseur研究”中的单一和多重剂量研究。