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 LLC已开发了一个新颖的平台，并确定了高度“有偏见”的脚步主义者镇痛药，但没有阿片类药物引起的不良反应。 Mebias的临床前研究比较了两种化合物， MEB-1166和MEB-1170，反对Trevena的橄榄石（TRV-130）和吗啡。以达到需要达到的剂量4倍相当于吗啡的ED80的有效性，两种MEBIAS化合物均未显示呼吸抑郁症，而吗啡橄榄石明显降低了呼吸功能。与吗啡相反，MEB-1166和MEB-1170均未产生了条件的地点偏好，表明滥用责任的吸收。本应用程序的UG3部分中概述的研究基于到目前为止收集的这些令人鼓舞的结果，并且是旨在提供对MEB-1166和MEB-1170的全面评估，以表征其药物和药理学特征以选择候选人进行辅助研究。我们还将进行虐待责任研究，在广泛的疼痛模型中检查镇痛活性。该提案的UG3部分完成后，我们预计MEB-1166或MEB-1170将进入本申请的UH3部分进行1阶段研究在“鉴赏家研究”中检查健康志愿者和虐待责任的单次和多次剂量研究。 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