TAAR1 Agonists as Narcolepsy Therapeutics

描述（由申请人提供）：嗜睡症折磨着0.025-0.05%的人群，其特征是白天过度嗜睡，猝睡（由情绪刺激引起的肌肉张力突然丧失），以及快速眼动（REM）睡眠的倾向增加。虽然嗜睡症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，但目前还没有小分子的可穿透脑的Hcrt受体激动剂用于下丘脑分泌素替代治疗。目前的治疗方法包括可能滥用的管制药物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，我们描述了一种新型的，可穿透大脑的微量胺相关受体1 （TAAR1）激动剂。这些化合物引起觉醒的剂量依赖性增加，减少快速眼动睡眠，并具有促进认知，抗抑郁和抗精神病样特性，表明TAAR1是除神经精神疾病外治疗病理性嗜睡的新靶点。在本研究中，我们将利用两种小鼠嗜睡症模型来验证TAAR1激动剂治疗嗜睡症的疗效。首先，我们将确定全部和部分TAAR1激动剂是否能促进食欲素/ataxin-3小鼠的觉醒、减少猝倒和使觉醒状态正常化，在这些小鼠中，Hcrt神经元已经过基因工程改造，在出生后退化。接下来，我们将在一种新的、可诱导的小鼠嗜睡症模型——食欲素/tTA中测试这些化合物；Tet-O DTA小鼠：通过四环素反激活剂（Tet-off）系统控制Hcrt神经元的消融，重现青春期后人类发作性睡病的发病过程。在每个模型中，我们将比较TAAR1激动剂与已知的促进苏醒的治疗性莫达非尼和抗弹片剂地西帕明的疗效。我们还将比较TAAR1拮抗剂对orexin/ataxin-3小鼠的剂量效应，以及对orexin/tTA小鼠的剂量效应；在发作性睡诱导前后，Tet-O DTA小鼠，以验证TAAR1激动作用使唤醒状态正常化的假设。TAAR1激动剂治疗发作性睡病的发现也将推动基于微量胺信号调节的促醒疗法的发展。

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.