Novel CNS Target for Sleep-Wake and Psychiatric Disorders

描述（由申请人提供）：行为、代谢和内分泌功能的昼夜节律调节是基本的稳态过程。生物钟的破坏与遗传和分子水平上的睡眠和精神疾病有关。我们在第一阶段启动了一项发现计划，以确定一种以前未开发的孤儿受体的配体，该受体直接与核心生物钟转录环相互作用。该受体主要在CNS中表达，并且在视交叉上核（SCN）中尤其突出，视交叉上核是提供昼夜节律功能的主要控制的下丘脑区域。基于基因敲除小鼠的表型，该受体在昼夜节律周期和情感障碍中起作用。能够改变SCN的相位或夹带和巩固来自SCN的信号的中枢作用小分子将在昼夜节律睡眠障碍（CRSD）中具有广泛的治疗潜力，所述昼夜节律睡眠障碍诸如延迟睡眠相位障碍（DSPD）、时差、轮班工作睡眠障碍和痴呆，其中睡眠-觉醒模式的破坏具有重大的经济和临床意义。褪黑激素及其类似物具有催眠作用和昼夜节律相移作用，但主要由于缺乏疗效而未广泛用于这些适应症。光作为时间疗法是有益的，但在给药方面存在实际问题。有相当大的潜力，更有效的计时。在第一阶段的支持下，我们开发了第一个筛选试验，发现了命中，并确定了具有良好效力（EC50 200 nM），血浆稳定性（终末半衰期= 1小时）和血脑屏障渗透（脑：血浆比= 1）的铅样配体。激动剂和拮抗剂直接调节BMAL1的启动子，一个核心时钟组件，如分子研究所预测的。我们在目标1中提出，对体内研究的电极导线进行最终优化，并研究分离SCN中昼夜节律循环的药理学调节，以模拟潜在的体内效应。在目标2中，我们通过在黑暗中24小时内自由奔跑的小鼠中短期暴露于配体来表征昼夜节律相移，这是潜在的计时器的经典测试。基于这些早期的研究结果，我们测试相移协议，可能指向临床实用性，如恒定夹带相对于光的睡眠相位障碍，或加速夹带后6小时的转变，在光暗周期类似时差。在目标3中，将在焦虑、抑郁和精神病模型中通过长期给药测试优化的电极导线。目前睡眠和精神疾病的治疗方法在有效性上不一致。本文所述的项目提供了第一次机会，以开发一个新的目标，已经出现了从生物钟分子机制的基础研究的时钟药物。睡眠障碍和精神疾病每年影响多达6000万美国人。治疗费用为2050亿美元/年，占美国年度医疗费用的15%。同时，目前的药物对于许多患者来说在治疗上是不充分的，并且基于少量的药物靶标。保持身体昼夜节律时间的转录时钟的分子成分直到最近才被认为广泛参与睡眠-觉醒障碍以及痴呆症，可能还有情绪和精神疾病。这种转录网络的调节可能对CNS治疗领域产生重大影响。

DESCRIPTION (provided by applicant): Circadian regulation of behavioral, metabolic, and endocrine function is a fundamental homeostatic process. Disruption of the circadian clock has been linked to sleep and psychiatric disorders at the genetic and molecular level. We initiated a discovery program in Phase I to identify ligands to a previously unexplored orphan receptor that directly interacts with the core circadian clock transcriptional loop. The receptor is expressed predominantly in the CNS and is especially prominent in the suprachiasmatic nucleus (SCN), the hypothalamic region that provides master control of circadian function. The receptor has a role in the circadian cycle and in affective disorders based on the phenotype of the knockout mouse. A centrally-acting small molecule that is capable of shifting the phase of the SCN, or entraining and consolidating signals from the SCN, will have widespread therapeutic potential in circadian rhythm sleep disorders (CRSDs) such as delayed sleep phase disorder (DSPD), jet lag, shift work sleep disorder, and dementia, where disruption of sleep-wake patterns is of major economic and clinical significance. Melatonin and its analogues, which have soporific as well as circadian phase-shifting effects, are not widely used in these indications, primarily due to lack of efficacy. Light is beneficial as chronotherapy but presents practical problems with administration. There is considerable potential for a more efficacious chronotherapeutic. With Phase I support we developed the first screening assays, discovered hits, and identified a lead-like ligand that has good potency (EC50 200 nM), plasma stability (terminal half-life = 1 hour) and blood-brain barrier penetration (brain:plasma ratio = 1). Agonists and antagonists directly regulate the promoter of BMAL1, a core clock component, as predicted by molecular studies. We propose in Aim 1 to carry out final optimization of a lead for in vivo studies and to investigate pharmacological regulation of circadian cycling in isolated SCN to model potential in vivo effects. In Aim 2, we characterize circadian phase shifting by short-term exposure to ligand in mice free running on a 24 h period in the dark, a classic test of a potential chronotherapeutic. Based on these early findings, we test phase shifting protocols that might point to clinical utility, such as constant entrainment with respect to light for a sleep phase disorder, or acceleration of entrainment following a 6 h shift in the light-dark cycle resembling jet lag. In Aim 3, an optimized lead will be tested by chronic dosing in models of anxiety, depression, and psychosis. Current therapies for sleep and psychiatric disorders are inconsistent in their effectiveness. The project described herein offers the first opportunity to develop chronotherapeutic drugs to a novel target that has emerged from fundamental investigations of the circadian clock molecular mechanisms. PUBLIC HEALTH RELEVANCE: Sleep disorders and mental illness affect up to 60 million Americans on an annual basis. The cost for treatment is $205 billion/year, accounting for 15% of annual U.S. healthcare costs. At the same time, current drugs are therapeutically inadequate for many patients and are based on small number of drug targets. The molecular components of the transcriptional clock that keeps the body's circadian time have been only recently recognized as having widespread involvement in sleep-wake disorders as well as dementia and perhaps mood and psychiatric disorders. Modulation of this transcriptional network could have a major impact in the area of CNS therapeutics.