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动态平衡过程。生物钟的紊乱在基因和分子水平上与睡眠和精神障碍有关。我们在第一阶段启动了一个发现计划，以确定一个先前未被探索的孤儿受体的配体，该受体直接与核心昼夜节律时钟转录环路相互作用。该受体主要在中枢神经系统表达，特别是在视交叉上核(SCN)，这是下丘脑的一个区域，提供对昼夜节律的主要控制。根据基因敲除小鼠的表型，该受体在昼夜节律和情感障碍中发挥作用。一种能够改变SCN的相位或携带和巩固来自SCN的信号的中枢作用小分子，将在睡眠相障碍(DSPD)、时差、轮班工作睡眠障碍和痴呆症等昼夜节律睡眠障碍(CRSD)中具有广泛的治疗潜力，这些睡眠-觉醒模式的中断具有重大的经济和临床意义。褪黑素及其类似物具有催眠和昼夜相移效应，但主要由于缺乏疗效，在这些适应症中并未广泛使用。光作为计时疗法是有益的，但在管理上存在实际问题。有相当大的潜力可以找到一种更有效的时间疗法。在第一阶段的支持下，我们开发了第一批筛选分析，发现了HITS，并确定了一种具有良好效力(EC50 200 NM)、血浆稳定性(终端半衰期=1小时)和血脑屏障穿透性(脑：血浆比=1)的类铅配体。正如分子研究预测的那样，激动剂和拮抗剂直接调节核心时钟成分BMAL1的启动子。在目标1中，我们建议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。在目标2中，我们通过在黑暗中自由运行24小时的小鼠短期暴露于配体来表征昼夜相变，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实用的相移方案，例如睡眠相紊乱时相对于光的持续夹带，或者类似于时差的明暗周期中6小时的移位后夹带的加速。在目标3中，优化的铅将在焦虑、抑郁和精神病模型中通过长期剂量进行测试。目前治疗睡眠和精神障碍的方法在有效性上是不一致的。这里描述的项目提供了第一次机会来开发针对生物钟分子机制的基础研究中出现的新靶点的时辰治疗药物。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。治疗成本为2050亿美元/年，占美国年度医疗成本的15%。与此同时，目前的药物对许多患者来说在治疗上是不够的，而且是基于少数药物靶点。直到最近，人们才认识到，保持人体昼夜节律的转录时钟的分子成分广泛参与了睡眠-觉醒障碍以及痴呆症，或许还有情绪和精神障碍。这一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.