A novel delta opioid receptor biased agonist for Major Depressive Disorder

一种治疗重度抑郁症的新型 δ 阿片受体偏向激动剂

• 批准号: 8522321
• 负责人: MICHAEL William LARK
• 金额: --
• 依托单位: TREVENA, INC.
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-08-15 至 2014-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8522321
• 关键词: Address; Adverse effects; Affect; Agonist; Analgesics; Anti-Anxiety Agents; Antidepressive Agents; Anxiety; Arrestins; Biological Assay; Biological Availability; Biological Testing; Biology; Brain; Characteristics; Chemistry; Clinic; Clinical; Clinical Data; Clinical Research; Clinical Trials; Consensus; Convulsions; Critical Pathways; Data; Development; Dose; Drug Kinetics; Elements; Endogenous depression; Environment; Fostering; Funding; GTP-Binding Proteins; Goals; Half-Life; High Prevalence; Human; In Vitro; Individual; Investigational New Drug Application; Lead; Ligands; Major Depressive Disorder; Medical; Mental Depression; Modeling; Neurosciences; Opioid; Opioid Receptor; Oral; Patients; Pharmaceutical Chemistry; Pharmaceutical Preparations; Phase; Phase I Clinical Trials; Primates; Principal Investigator; Property; Quality of life; Receptor Activation; Receptor Signaling; Recording of previous events; Research; Rodent; Safety; Seizures; Shapes; Signal Transduction; Swimming; Testing; Therapeutic; Time; United States National Institutes of Health; Work; base; chronic pain; delta opioid receptor; design; drug candidate; drug development; experience; in vivo; meetings; novel; novel strategies; novel therapeutics; pre-clinical; programs; receptor; scaffold; screening; small molecule; volunteer

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.

描述（由申请人提供）：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使一半的患者得到缓解，而且只有在治疗数周后才能缓解，并且不良反应的发生率很高。 δ-阿片受体激动剂是在啮齿类动物中起效快的抗抑郁药，并且具有镇痛和抗焦虑作用。它们可能提供一种有价值的新方法来治疗重度抑郁症，特别是相当大一部分患有焦虑症或慢性疼痛的重度抑郁症患者。不幸的是，δ-阿片受体激动剂也会引起啮齿类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。它们还表现出受耐受性限制的短暂功效。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通过一类称为“偏向配体”的特殊激动剂来分开，该激动剂仅选择性地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 δ-阿片受体偏向配体，该配体能够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的是，它不会与 p-arrestin 结合，从而促进耐受性和惊厥。该分子对 δ-阿片受体具有选择性，并具有适合优化为新药物分子的特性。通过与 NIH Blueprint for Neuroscience Grand Challenge 合作，该项目旨在进行体外和体内药物化学和生物测试的迭代循环，以获得具有适当功效和安全性的候选药物，以便向美国提交研究性新药申请。 FDA 和一项 I 期临床研究旨在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化合物，该化合物具有令人信服的临床前概念证明，可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支持患者测试。这些数据将非常适合吸引更多资金或合作伙伴进行进一步的临床试验和新药申请，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。