TAAR1 agonists as wake-promoting and cognitive-enhancing therapeutics

描述（由申请人提供）：本提案的目的是确定微量胺相关受体1 （TAAR1）的配体是否像我们在实验室啮齿动物中发现的那样，在非人灵长类动物中促进觉醒和促进认知。最近发现的TAAR1选择性激动剂在啮齿类动物和非人类灵长类动物中均表现出促进认知、抗抑郁和抗精神病样特性，这表明TAAR1是治疗神经精神疾病的新靶点。在与F. Hoffmann-La Roche的科学家合作中，我们描述了对小鼠、大鼠、猴子和人类TAAR1具有高效和选择性的可穿透大脑的化合物。此外，我们发现TAAR1激动作用导致大鼠清醒程度的剂量依赖性增加，并在小鼠中复制了这一效应。鉴于睡眠障碍的广泛发生，我们将进一步验证TAAR1激动作用是促进清醒和增强认知的新治疗途径的假设。首先，我们将确定TAAR1激动作用是否会促进食蟹猴在高睡眠压力和低睡眠压力条件下的觉醒。虽然TAAR1激动剂提高了啮齿动物的警觉性，但与人类和非人类灵长类动物的睡眠和清醒合并期特征相比，这些动物是夜行动物，具有多相睡眠/觉醒周期。在这些研究中实施脑电图记录将使我们能够确定TAAR1激动剂对NREM和REM睡眠的影响，并进行定量脑电图（qEEG）分析，以评估这些化合物对与认知相关的脑电图频率（如伽马振荡）的影响。接下来，我们将测试这些化合物在基线和睡眠剥夺条件下改善猕猴工作记忆功能的能力。工作记忆功能依赖于先前的睡眠历史，并受年龄、压力和精神分裂症和阿尔茨海默病等疾病的影响而下降。我们之前已经证明，TAAR1激动剂可以改善非人类灵长类动物和啮齿动物pcp诱导的缺陷模型中的执行功能（例如，反应抑制，计划），然而，这只代表了睡眠障碍中可能受到影响的一个认知领域。同时评估执行工作记忆任务的猕猴的行为和qEEG将有助于在行为和电生理水平上研究认知功能。这些研究的结果将有助于建立TAAR1激动作用作为一种新的机制来增强人类的觉醒和认知。

DESCRIPTION (provided by applicant): The goal of this proposal is to determine whether ligands for Trace Amine-associated Receptor 1 (TAAR1) are wake-promoting and pro-cognitive in non-human primates as we have found in laboratory rodents. Recent identification of selective agonists for TAAR1 that exhibit pro-cognitive, antidepressant- and antipsychotic-like properties in both rodent and non-human primates suggest TAAR1 is a novel target for the treatment of neuropsychiatric disorders. In collaboration with scientists from F. Hoffmann-La Roche, we have described brain-penetrable compounds with high potency and selectivity at mouse, rat, monkey and human TAAR1. Moreover, we showed that TAAR1 agonism causes a dose-dependent increase in wakefulness in rats and have replicated this effect in mice. Given the widespread occurrence of sleep disorders, we will further test the hypothesis that TAAR1 agonism is a novel therapeutic pathway to promote wake and enhance cognition. First, we will determine whether TAAR1 agonism promotes wakefulness in Cynomolgus macaques under conditions of both high and low sleep pressure. Although TAAR1 agonists increase vigilance in rodents, these animals are nocturnal and have polyphasic sleep/wake cycles in comparison to the consolidated periods of sleep and wakefulness characteristic of both humans and non-human primates. Implementation of EEG recording in these studies will enable us to determine the effects of TAAR1 agonism on NREM and REM sleep and to conduct quantitative EEG (qEEG) analysis to assess the effects of these compounds on EEG frequencies associated with cognition such as gamma oscillations. Next, we will test these compounds for their ability to improve working memory functions in macaques under baseline and sleep deprivation conditions. Working memory function is dependent on prior sleep history and subject to decline in aging, stress and in diseases such as schizophrenia and Alzheimer's disease. We have shown previously that TAAR1 agonists improve executive functions (e.g., response inhibition, planning) in non-human primates and in a rodent PCP-induced deficit model, however, this represents only one cognitive domain that can be affected in sleep disorders. Simultaneous assessment of behavior and qEEG in macaques performing the working memory task will enable investigation of cognitive function at both behavioral and electrophysiological levels. The results of these studies will aid in establishing TAAR1 agonism as a novel mechanism to enhance wakefulness and cognition in humans.