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

• 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
• 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

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’.

美国大约有1亿人患有疼痛，其中900万到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和复杂的公共卫生挑战。阿片类药物过量是美国意外死亡的主要原因，估计每天有100人因呼吸抑制而死于阿片类药物过量。虽然阿片类药物使用和滥用的增加无疑是由多种因素造成的，但迫切需要一种有效的阿片类镇痛药，同时还能解决与阿片类药物滥用责任和过量死亡有关的重大问题。我们对g蛋白偶联受体信号传导相关的药理学机制的理解取得了进展，这导致了对mu-阿片受体激活的认识