TAAR1 Agonists as Narcolepsy Therapeutics

描述（由申请人提供）：发作性睡病折磨0.025-0.05%的人群，其特征为白天过度嗜睡、紧张性昏厥（由情绪刺激引发的肌肉张力突然丧失）和快速眼动（REM）睡眠倾向增加。虽然发作性睡病是由产生下丘脑泌素（Hcrt;也称为食欲素）的神经元变性引起的，但目前没有小分子脑穿透性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有滥用可能的受管制药物或有其他不良副作用的药物。在刚刚发表的论文中，来自F。Hoffmann-LaRoche，我们描述了一种新型的、脑可穿透的痕量胺相关受体1（TAAR 1）激动剂。这些化合物引起觉醒的剂量依赖性增加，减少REM睡眠，并具有促认知、抗抑郁和抗精神病样性质，表明TAAR 1是除神经精神障碍外治疗病理性嗜睡的新靶标。在这个提议中，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TAAR 1激动剂作为治疗发作性睡病的治疗功效。首先，我们将确定是否完全和部分TAAR 1激动剂促进觉醒，减少catabolism和正常的唤醒状态食欲素/共济失调蛋白-3小鼠，其中Hcrt神经元已被基因工程退化出生后。接下来，我们将测试这些化合物在一个新的，诱导模型的小鼠发作性睡病的食欲素/tTA; Tet-O DTA小鼠，其中消融的Hcrt神经元控制通过四环素反式激活（Tet-off）系统，以重演青春期后发作的人类发作性睡病。在每个模型中，我们将比较TAAR 1激动剂与已知的促醒治疗剂莫达非尼和抗惊厥剂地昔帕明的疗效。我们还将比较食欲素/共济失调蛋白-3小鼠与野生型同窝出生小鼠中以及食欲素/tTA; Tet-O DTA小鼠在嗜睡症诱导之前和之后TAAR 1激动的剂量反应效应，以检验TAAR 1激动使觉醒状态正常化的假设。用于治疗发作性睡病的TAAR 1激动剂的发现也将推进基于微量胺信号传导的调节的促醒疗法的开发。

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.