TAAR1 Agonists as Narcolepsy Therapeutics

TAAR1 激动剂作为发作性睡病治疗药物

• 批准号: 8565060
• 负责人: SARAH WURTS BLACK
• 金额: $ 29.45万
• 依托单位: SRI INTERNATIONAL
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-08-01 至 2015-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8565060
• 关键词: Ablation; Advanced Development; Adverse effects; Affect; Age; Agonist; Amines; Amphetamines; Animal Model; Animals; Anti-Cholinergics; Antidepressive Agents; Antipsychotic Agents; Arousal; Binding; Biogenic Amines; Brain; Cataplexy; Cells; Cerebrospinal Fluid; Cognitive; Collaborations; Dependency; Desipramine; Development; Diet; Disease; Doctor of Philosophy; Dose; Doxycycline; Drug Industry; Emotional; Excessive Daytime Sleepiness; Excision; G-Protein-Coupled Receptors; Genetic Engineering; Goals; Human; Hypothalamic structure; Incidence; Lateral; Life; MJD1 protein; Modafinil; Modeling; Mus; Muscle Tonus; Narcolepsy; Nerve Degeneration; Neurodegenerative Disorders; Neurons; Neurosciences; Onset of illness; Paper; Patients; Peptides; Pharmaceutical Preparations; Phenotype; Population; Property; Proteins; Puberty; Publishing; REM Sleep; Rare Diseases; Rattus; Regimen; Replacement Therapy; Research; Rodent; Scientist; Signal Transduction; Sleep; Sleep Disorders; Societies; Symptoms; System; Testing; Tetanus Helper Peptide; Tetracyclines; Therapeutic; Time; Trans-Activators; Transgenic Organisms; Treatment Efficacy; Wakefulness; Wild Type Mouse; base; comparative efficacy; gamma hydroxybutyrate; hypocretin; interest; meetings; mouse model; neuron loss; neuropsychiatry; neurotoxic; novel; novel therapeutics; orexin A receptor; phase 1 study; postnatal; programs; promoter; public health relevance; receptor; receptor binding; response; sleep abnormalities; small molecule; therapeutic target; vigilance

DESCRIPTION (provided by applicant): Narcolepsy afflicts 0.025-0.05% of the population and is characterized by excessive daytime sleepiness, cataplexy (a sudden loss of muscle tone triggered by emotional stimulation), and increased propensity for rapid-eye-movement (REM) sleep. Although narcolepsy results from degeneration of neurons that produce hypocretin (Hcrt; also known as orexin), no small-molecule brain-penetrable Hcrt receptor agonists currently exist for hypocretin replacement therapy. Current treatments include controlled substances with abuse potential or drugs with other undesirable side effects. In papers just published with scientists from F. Hoffmann- LaRoche, we describe novel, brain-penetrable agonists for Trace Amine-associated Receptor 1 (TAAR1). These compounds cause a dose-dependent increase in wakefulness, reduce REM sleep, and have pro- cognitive, antidepressant- and antipsychotic-like properties, suggesting TAAR1 as a novel target for the treatment of pathological sleepiness in addition to neuropsychiatric disorders. In this proposal, we will determine the therapeutic efficacy of TAAR1 agonism as a treatment for narcolepsy in proof-of-concept studies using two murine narcolepsy models. First, we will determine whether full and partial TAAR1 agonists promote wakefulness, reduce cataplexy and normalize arousal states in the orexin/ataxin-3 mouse, in which Hcrt neurons have been genetically engineered to degenerate postnatally. Next, we will test these compounds in a novel, inducible model of murine narcolepsy-the orexin/tTA; Tet-O DTA mouse-in which ablation of Hcrt neurons is controlled through the tetracycline transactivator (Tet-off) system to recapitulate the post-pubertal onset of human narcolepsy. In each model, we will compare the efficacy of TAAR1 agonists against the known wake-promoting therapeutic modafinil and anti-cataplectic agent desipramine. We will also compare the dose- response effects of TAAR1 agonism in orexin/ataxin-3 mice with wild-type littermates, and in orexin/tTA; Tet-O DTA mice before and after narcolepsy induction, to test the hypothesis that TAAR1 agonism normalizes arousal states. Discovery of TAAR1 agonists for the treatment of narcolepsy will also advance the development of wake-promoting therapeutics based on modulation of trace amine signaling.

描述（由申请人提供）：嗜睡症困扰着 0.025-0.05% 的人口，其特点是白天过度嗜睡、猝倒（情绪刺激引发的肌张力突然丧失）以及快速眼动 (REM) 睡眠倾向增加。尽管发作性睡病是由产生下丘脑分泌素（Hcrt；也称为食欲素）的神经元退化引起的，但目前尚不存在可用于下丘脑分泌素替代疗法的小分子可穿透大脑的 Hcrt 受体激动剂。目前的治疗方法包括具有滥用潜力的受控物质或具有其他不良副作用的药物。在刚刚与 F. Hoffmann-LaRoche 的科学家合作发表的论文中，我们描述了痕量胺相关受体 1 (TAAR1) 的新型脑可穿透激动剂。这些化合物会导致觉醒程度呈剂量依赖性增加，减少快速眼动睡眠，并具有促认知、抗抑郁和抗精神病样特性，表明 TAAR1 除了神经精神疾病外，还可以作为治疗病理性嗜睡的新靶点。在本提案中，我们将使用两种小鼠发作性睡病模型进行概念验证研究，以确定 TAAR1 激动剂作为治疗发作性睡病的治疗效果。首先，我们将确定完全和部分 TAAR1 激动剂是否可以促进 orexin/ataxin-3 小鼠的觉醒、减少猝倒并使唤醒状态正常化，其中 Hcrt 神经元经过基因工程改造，在出生后退化。接下来，我们将在小鼠发作性睡病的新型诱导模型——食欲素/tTA 中测试这些化合物； Tet-O DTA 小鼠，其中 Hcrt 神经元的消融是通过四环素反式激活子 (Tet-off) 系统控制的，以重现人类发作性睡病的青春期后发作。在每个模型中，我们将比较 TAAR1 激动剂与已知的促醒治疗药物莫达非尼和抗惊厥药物地昔帕明的功效。我们还将比较 TAAR1 激动剂对 orexin/ataxin-3 小鼠与野生型同窝小鼠以及 orexin/tTA 的剂量反应效应； Tet-O DTA 小鼠在发作性睡病诱导之前和之后，以测试 TAAR1 激动使觉醒状态正常化的假设。用于治疗发作性睡病的 TAAR1 激动剂的发现也将促进基于微量胺信号传导调节的唤醒疗法的开发。