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一个基本的体内平衡过程。在遗传和分子水平上，生物钟的紊乱与睡眠和精神疾病有关。我们在第一阶段启动了一个发现项目，以确定一个以前未被发现的孤儿受体的配体，该受体直接与核心生物钟转录环相互作用。该受体主要在中枢神经系统中表达，尤其在视交叉上核（SCN）中表达，视交叉上核是控制昼夜节律功能的下丘脑区域。该受体在昼夜节律周期和基于敲除小鼠表型的情感障碍中发挥作用。一种中枢作用的小分子，能够改变SCN的阶段，或携带和巩固来自SCN的信号，将在昼夜节律睡眠障碍（crsd）中具有广泛的治疗潜力，如延迟睡眠阶段障碍（DSPD）、时差反应、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要的经济和临床意义。褪黑素及其类似物具有催眠作用和昼夜节律相移作用，但由于缺乏疗效，并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，更有效的时间治疗。在I期的支持下，我们开发了第一个筛选试验，发现了命中点，并确定了一种具有良好效力（EC50 200 nM），血浆稳定性（终末半衰期= 1小时）和血脑屏障穿透性（脑：血浆比率= 1）的铅样配体。正如分子研究预测的那样，激动剂和拮抗剂直接调节BMAL1的启动子，BMAL1是一个核心时钟组件。在Aim 1中，我们建议对一种先导物进行体内研究的最终优化，并研究分离的SCN中昼夜循环的药理学调节，以模拟潜在的体内效应。在Aim 2中，我们通过在黑暗中自由奔跑24小时的小鼠中短期暴露于配体来表征昼夜节律相转移，这是一种潜在的时间治疗的经典测试。基于这些早期的发现，我们测试了可能指向临床应用的相移方案，例如在睡眠阶段障碍中持续的光夹带，或者在类似于时差的光-暗周期变化6小时后加速夹带。在Aim 3中，优化的铅将通过慢性给药在焦虑、抑郁和精神病模型中进行测试。目前治疗睡眠和精神疾病的方法在有效性上是不一致的。本文所描述的项目提供了第一个开发时间治疗药物的机会，该药物是针对昼夜节律钟分子机制的基础研究中出现的新靶标。公共卫生相关性：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，占美国年度医疗保健费用的15%。与此同时，目前的药物对许多患者的治疗不足，并且基于少量的药物靶点。维持人体昼夜节律的转录钟的分子成分直到最近才被认识到在睡眠-觉醒障碍、痴呆、情绪和精神障碍中有广泛的参与。这种转录网络的调节可能在中枢神经系统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.