TAAR1 agonists as wake-promoting and cognitive-enhancing therapeutics

TAAR1 激动剂作为唤醒促进和认知增强疗法

• 批准号: 8906960
• 负责人: Thomas S Kilduff
• 金额: $ 47.36万
• 依托单位: SRI INTERNATIONAL
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-08-15 至 2017-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8906960
• 关键词: Affect; Aging; Agonist; Alzheimer' s Disease; Amines; Amino Acids; Animals; Antidepressive Agents; Antipsychotic Agents; Attention; Behavior assessment; Behavioral; Biogenic Amines; Biological Psychiatry; Brain; Caffeine; Characteristics; Cognition; Cognition Disorders; Cognitive; Collaborations; Development; Disease; Dose; Down-Regulation; Electroencephalography; Emotions; Exhibits; Frequencies; G-Protein-Coupled Receptors; Glutamates; Goals; Health; Human; Human Characteristics; Investigation; Laboratories; Ligands; Light; Macaca; Modeling; Molecular; Monkeys; Mus; Octopamine; Paper; Pathway interactions; Performance; Pharmacotherapy; Phase; Phenethylamines; Process; Property; Psychiatry; Publishing; REM Sleep; Rattus; Recording of previous events; Relative (related person); Research; Rodent; Schizophrenia; Scientist; Serotonin; Short-Term Memory; Sleep; Sleep Deprivation; Sleep Disorders; Sleep Wake Cycle; Stress; Testing; Therapeutic; Time; Tryptamines; Tyramine; Wakefulness; abstracting; cognitive function; efficacy testing; executive function; flexibility; improved; neuropsychiatry; new therapeutic target; nonhuman primate; novel; novel therapeutics; pressure; receptor; response; vigilance

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.

描述（由申请人提供）：本提案的目标是确定痕量胺相关受体 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类灵长类动物中具有促进唤醒和促进认知的作用。最近鉴定的 TAAR1 选择性激动剂在啮齿动物和非人类灵长类动物中表现出促认知、抗抑郁和抗精神病样特性，表明 TAAR1 是治疗神经精神疾病的新靶点。我们与 F. Hoffmann-La Roche 的科学家合作，描述了对小鼠、大鼠、猴子和人类 TAAR1 具有高效力和选择性的可穿透大脑的化合物。此外，我们发现 TAAR1 激动剂会导致大鼠的觉醒程度呈剂量依赖性增加，并在小鼠中复制了这种效应。鉴于睡眠障碍的广泛发生，我们将进一步检验 TAAR1 激动剂是一种促进觉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。尽管 TAAR1 激动剂可以提高啮齿动物的警惕性，但这些动物是夜间活动的，与人类和非人类灵长类动物的睡眠和觉醒特征的综合周期相比，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（如伽马振荡）相关的脑电图频率的影响。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。工作记忆功能取决于先前的睡眠史，并且会因衰老、压力以及精神分裂症和阿尔茨海默病等疾病而下降。我们之前已经表明，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，这仅代表睡眠障碍中可能受到影响的一个认知领域。对执行工作记忆任务的猕猴的行为和 qEEG 进行同时评估将能够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将 TAAR1 激动作用确立为增强人类觉醒和认知的新机制。

项目成果

Trace Amine-Associated Receptor 1 Agonists as Narcolepsy Therapeutics.

• DOI: 10.1016/j.biopsych.2016.10.012
• 发表时间: 2017-11-01
• 期刊: Biological psychiatry
• 影响因子: 10.6
• 作者: Black SW;Schwartz MD;Chen TM;Hoener MC;Kilduff TS
• 通讯作者: Kilduff TS

Trace Amine-Associated Receptor 1 Regulates Wakefulness and EEG Spectral Composition.

微量胺相关受体 1 调节清醒状态和脑电图频谱组成。

• DOI: 10.1038/npp.2016.216
• 发表时间: 2017
• 期刊: Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology
• 作者: Schwartz,MichaelD;Black,SarahW;Fisher,SimonP;Palmerston,JeremiahB;Morairty,StephenR;Hoener,MariusC;Kilduff,ThomasS
• 通讯作者: Kilduff,ThomasS