TAAR1 Agonists as Narcolepsy Therapeutics

TAAR1 激动剂作为发作性睡病治疗药物

基本信息

批准号：
8697159
负责人：
Thomas S Kilduff
金额：
$ 24.51万
依托单位：
SRI INTERNATIONAL
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-08-01 至 2016-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8697159
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

项目摘要

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）：发作性疾病折磨于0.025-0.05％的人口，其特征是白天昏昏欲睡，脱发（突然因情绪刺激引起的肌肉张力突然丧失）和快速眼睛移动（REM）睡眠的倾向增加。尽管发作性疾病是由于产生低载素的神经元的变性（HCRT；也称为Orexin），但目前目前没有用于替代毒素替代疗法的小分子脑部脑部 - 脑部脑渗透HCRT受体激动剂。当前的治疗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。在刚刚与霍夫曼·拉洛奇（F. Hoffmann-Laroche）的科学家发表的论文中，我们描述了针对痕量胺相关受体1（TAAR1）的新颖，可脑渗透激动剂。这些化合物会导致剂量依赖性的清醒升高，减少REM睡眠，并具有认知，抗抑郁药和抗精神病药样特性，这表明TAAR1是治疗神经精神疾病外治疗病理性嗜睡的新目标。在此提案中，我们将使用两种鼠类性睡病模型来确定TAAR1激动剂作为对概念验证研究的治疗疗法的治疗功效。首先，我们将确定在Orexin/ataxin-3小鼠中是否会促进清醒，降低催化性并归一化唤醒状态，其中HCRT神经元在遗传上进行了基因工程，以在后期进行脱位。接下来，我们将在一种新颖的鼠性蠕虫病蛋白/TTA的新颖的，可诱导的模型中测试这些化合物。 TET-O DTA鼠标in，通过四环素反式激活器（TET-OFF）系统控制HCRT神经元的消融，以概括人性疾病的素后发作。在每个模型中，我们将比较TAAR1激动剂与已知的促唤醒莫达非尼和抗cataplectic剂去丙胺的疗效。我们还将比较taar1激动剂在Orexin/ataxin-3小鼠中的剂量反应作用与野生型同窝仔，以及Orexin/tta中的剂量反应作用；诱导性发育迟缓之前和之后的TET-O DTA小鼠，以检验Taar1激动剂使唤醒状态归一化的假设。基于痕量胺信号传导的调节，发现TAAR1激动剂用于治疗睡病的治疗也将推动促进唤醒治疗剂的发展。