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: 8316155
• 负责人: MICHAEL William LARK
• 金额: $ 15.44万
• 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 2016-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8316155
• 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; Screening procedure; 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; 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针对重度抑郁症（MDD）的新疗法，该疗法每年影响4000万人，从而极大地降低生活质量。当前的治疗只能减轻一半的患者，然后仅经过数周的治疗，并且患病率很高。三角洲阿片受体的激动剂是抗抑郁药，啮齿动物的发作迅速，是镇痛和抗焦虑。他们可能会提供一种有价值的新方法来治疗MDD，尤其是也遭受焦虑或慢性疼痛的MDD患者的大部分。不幸的是，三角洲阿片类激动剂也引起了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工作。它们还显示瞬态疗效受耐受性的限制。然而，最近的数据表明，三角洲阿片受体激活的治疗，耐受性和抽搐作用可以通过一种称为“偏置配体”的特殊类型的激动剂分离，该类别仅有选择地与标准激动剂通常刺激的受体信号的一部分。该项目基于一种新型的三角洲 - 阿片受体偏见的配体，该配体有效，可靠地激活治疗性G蛋白信号传导，但与标准激动剂不同，它不吸引p-arrestin，从而促进耐受性和抽搐。该分子对三角洲阿片受体具有选择性，并且具有适合优化新药分子的特征。 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.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，以快速发作抗抑郁药，并有可能具有抗焦虑和镇痛特性，并具有早期的临床数据，以支持患者的测试。这些数据将是吸引进一步的临床试验的进一步资金或合作伙伴关系的理想选择，并为数百万患有MDD的患者提供有价值的新疗法。