TAAR1 Agonists as Narcolepsy Therapeutics

描述(申请人提供)：发作性睡病困扰0.025-0.05%的人口，其特征是白天过度嗜睡、猝倒(由情绪刺激引发的肌肉张力突然丧失)，以及快速眼动睡眠倾向增加。虽然发作性睡病是由于产生下丘脑泌素(Hcrt；也称为增食欲素)的神经元退化所致，但目前还没有可穿透大脑的小分子Hcrt受体激动剂用于下丘脑泌素替代疗法。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的科学家发表的论文中，我们描述了新颖的、可穿透大脑的痕量胺相关受体1(TAAR1)激动剂。这些化合物会引起剂量依赖性的觉醒增加，减少REM睡眠，并具有促进认知、抗抑郁和抗精神病药物样的特性，这表明TAAR1是除神经精神障碍外治疗病理性嗜睡的新靶点。在这项提案中，我们将使用两种小鼠发作性睡病模型，在概念验证研究中确定TAAR1激动剂治疗发作性睡病的疗效。首先，我们将确定在增食欲素/ataxin-3小鼠中，全部和部分TAAR1激动剂是否促进觉醒，减少猝倒，并使唤醒状态正常化，在这些小鼠中，Hcrt神经元已被基因工程改造为出生后退化。接下来，我们将在一种新颖的、可诱导的小鼠发作性睡病模型-食欲素/TTA；Tet-O DTA小鼠中测试这些化合物，在该模型中，Hcrt神经元的消融通过四环素反式激活因子(Tet-Off)系统来控制，以概括人类青春期后发作性睡病的情况。在每个模型中，我们将比较TAAR1激动剂与已知的促进觉醒的治疗药物莫达非尼和抗剥脱剂地昔帕明的疗效。我们还将比较TAAR1激动剂在野生型窝仔中的剂量-反应效应，以及在诱发发作性睡病之前和之后在oresin/TTA；Tet-O DTA小鼠中的剂量-反应效应，以验证TAAR1激动剂可使觉醒状态正常化的假设。TAAR1激动剂用于治疗发作性睡病的发现也将促进基于微量胺信号调节的觉醒疗法的发展。

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.