A novel delta opioid receptor biased agonist for Major Depressive Disorder

该项目旨在发现和开发一种治疗重度抑郁症（MDD）的新疗法，该疾病每年影响4000万人，严重降低生活质量。目前的治疗方法只能缓解一半的患者，而且只能在治疗数周后才能缓解，而且不良反应的发生率很高。δ-阿片受体激动剂是抗抑郁药，在啮齿类动物中起效迅速，并具有镇痛和抗焦虑作用。它们可能为治疗MDD提供一种有价值的新方法，特别是相当大一部分MDD患者也患有焦虑或慢性疼痛。不幸的是，δ-阿片激动剂也会导致啮齿动物和灵长类动物的惊厥，这阻碍了迄今为止的药物开发工作;它们还显示出受耐受性限制的短暂疗效。然而，最近的数据表明，δ-阿片受体激活的治疗、耐受和惊厥作用可以被称为“偏向配体”的一类特殊激动剂分开，所述偏向配体选择性地仅参与通常由标准激动剂刺激的受体信号的子集。该项目基于一种新型的δ-阿片受体偏向配体，该配体有效且稳健地激活治疗性G蛋白信号传导，但与标准激动剂不同，它不参与促进耐受性和惊厥的β-抑制蛋白。该分子对δ-阿片受体具有选择性，并具有适合于优化成新药分子的特征。通过与NIH Blueprint for Neuroscience Grand Challenge的合作，该项目旨在参与体外和体内药物化学和生物学测试的迭代周期，以获得具有适当疗效和安全性的候选药物，以便向美国FDA提交研究性新药申请，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明的化合物，用于快速起效的抗抑郁药，可能具有抗焦虑和镇痛特性，并具有早期临床数据以支持患者测试。这些数据将是吸引更多资金或合作伙伴进行进一步临床试验和新药申请的理想选择，为数百万患有MDD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.