A novel delta opioid receptor biased agonist for Major Depressive Disorder

项目描述（由申请人提供）：本项目旨在发现和开发一种新的治疗重度抑郁症（MDD）的方法，每年有4000万人受到影响，严重降低了生活质量。目前的治疗方法只能缓解一半的患者，而且只有在治疗数周后才能缓解，而且副作用的发生率很高。阿片受体激动剂在啮齿类动物中具有快速起效的抗抑郁作用，并且具有镇痛和抗焦虑作用。它们可能为治疗重度抑郁症，尤其是相当大一部分同时遭受焦虑或慢性疼痛的重度抑郁症患者提供了一种有价值的新方法。不幸的是，阿片受体激动剂也会引起啮齿动物和灵长类动物的抽搐，这阻碍了迄今为止的药物开发努力；它们也表现出受耐受性限制的短暂疗效。然而，最近的数据表明，三角洲阿片受体激活的治疗、耐受性和惊厥作用可以被一类称为“偏倚配体”的激动剂分开，这种激动剂只选择性地参与通常由标准激动剂刺激的受体信号的一部分。该项目基于一种新型的δ -阿片受体偏配体，该配体有效且稳健地激活治疗性G蛋白信号，但与标准激动剂不同的是，它不参与促进耐受性和抽搐的p-骤停素。该分子对阿片受体具有选择性，具有适合优化为新药分子的特性。通过与美国国立卫生研究院神经科学大挑战蓝图的合作，该项目旨在进行体外和体内药物化学和生物学测试的迭代循环，以获得具有适当疗效和安全性的候选药物，从而允许向美国FDA提交新药研究申请，并进行I期临床研究，以测试该化合物在正常志愿者中的药代动力学、安全性和耐受性。该项目的成功完成将提供一种具有令人信服的临床前概念证据的化合物，作为一种快速起效的抗抑郁药，具有潜在的抗焦虑和镇痛特性，以及早期临床数据，以支持在患者中进行测试。这些数据将为进一步的临床试验和新药申请吸引更多的资金或合作伙伴，从而为数百万患有重度抑郁症的患者提供有价值的新疗法。

DESCRIPTION (provided by applicant): This project aims to discover and develop a new therapy for major depressive disorder (MDD), which affects 40 million people annually, profoundly reducing quality of life. Current treatments offer relief to only half of patients, and then only after weeks of treatment and with a high prevalence of adverse effects. Agonists of the delta-opioid receptor are antidepressant with rapid onset in rodents, and are analgesic and anxiolytic. They may offer a valuable new approach to treating MDD and in particular the sizeable fraction of MDD patients who also suffer anxiety or chronic pain. Unfortunately, delta-opioid agonists also cause convulsions in rodents and primates, which have thwarted drug development efforts to date; they also display transient efficacy limited by tolerance. However, recent data suggest that therapeutic, tolerizing, and convulsive effects of the delta-opioid receptor activation can be separated by a special class of agonist called "biased ligands", which selectively engage only a subset of the receptor signals normally stimulated by standard agonists. This project is based on a novel delta-opioid receptor biased ligand that potently and robustly activates therapeutic G protein signaling, but unlike standard agonists does not engage p-arrestin, which promotes tolerance and convulsions. This molecule is selective for the delta-opioid receptor and has characteristics appropriate for optimization into a new drug molecule. Through partnership with the NIH Blueprint for Neuroscience Grand Challenge, this project aims to engage iterative cycles of medicinal chemistry and biological testing in vitro and in vivo to derive a candidate drug with appropriate efficacy and safety to permit filing an Investigational New Drug application with the U.S. FDA and a Phase I clinical study to test pharmacokinetics, safety, and tolerability of the compound in normal volunteers. Successful completion of this project will deliver a compound with compelling preclinical proof of concept for a rapid onset antidepressant, potentially with anxiolytic and analgesic properties, with early clinical data to support testing in patients. This data will be ideal to attract further funding or partnership for further clinical trials and a New Drug Application to deliver a valuable new therapy to the millions of patients suffering from MDD.