Discovery of Selective MT1 Melatonin Receptor Ligands for Sleep Disorders

描述(由申请人提供)： 由压力、疾病、慢性疼痛和不良睡眠习惯引起的睡眠障碍是一个主要的社会和健康问题，会导致失业、注意力和生产力下降、白天昏昏欲睡、身体不协调，并经常导致严重事故。目前，这些睡眠障碍的治疗方法是非处方药或处方催眠药。然而，其中一些药物显示出明显的副作用，包括镇静、记忆问题、头痛、停止性失眠和梦游，还可能形成习惯。褪黑激素是松果体以昼夜节律方式分泌的一种神经激素，通过激活两个膜结合的G蛋白偶联受体：MT1和MT2来促进睡眠和调节昼夜节律。褪黑素受体激动剂代表了一类新的药物，用于治疗非镇静和非成瘾的失眠和昼夜睡眠障碍，Ramelteon是第一个在美国上市的非选择性MT1/MT2褪黑素受体激动剂。我们的目标是设计口服活性、高亲和力和选择性的褪黑素受体激动剂，具有最佳的药理、药代动力学和代谢特征，以建立概念证据，并进一步研究这一系列化合物在促进睡眠和相移改变昼夜节律方面的有效性，同时将持续的褪黑素受体脱敏/内化导致的潜在副作用降至最低。为了实现这些目标，我们将：1)反复开发计算策略和化学合成，以确定新的化学支架(核心)，并提高MT1褪黑素受体的配基效能和选择性，随后通过基于电子配基的发现(使用药效团)、虚拟筛选、定量结构活性关系和比较分子场分析来选择候选分子；2)利用哺乳动物细胞中表达的35S-GTP-3-S与hMT1和hMT2受体的结合和刺激，确定配体亲和力、激动剂效力和受体选择性；3)评估先导化合物的稳定性、脑渗透性和口服生物利用度；4)测定铅化合物对小鼠视交叉上核(SCN)脑片表达的褪黑素受体MT1和/或MT2的功能效应(即抑制神经元放电、改变神经元放电昼夜节律的相移)和小鼠体内模型(即相移活动节律开始)。西北大学和Tougaloo研究人员之间的这个合作项目将融合药物化学、基于计算和结构的药物发现以及体外和体内模型筛选方面的专业知识，以评估先导化合物的亲和力、效力和选择性。我们将共同努力，最大限度地发现急需的研究工具(即MT1选择性配体)和具有功能活性的MT1主要褪黑素受体激动剂系列，未来有可能用于治疗失眠和昼夜睡眠障碍，如睡眠延迟综合征、盲人和时差。 公共卫生相关性： 由于压力、疾病、慢性疼痛、精神疾病和不良睡眠习惯导致的睡眠障碍影响着美国7000万人，经常导致昏昏欲睡、身体不协调以及严重的机动车和其他事故。这项提议的目标是发现一种药物，它将模仿褪黑激素的效果，可以用来促进睡眠，并治疗由抑郁症、帕金森氏症、失明、时差、倒班和其他相关疾病引起的睡眠障碍。

DESCRIPTION (provided by applicant): Sleep disorders due to stress, illness, chronic pain, and poor sleep habits are a major social and health concern, resulting in lost work, decreased attention and productivity, daytime drowsiness, incoordination, and often leading to serious accidents. At present, these sleep disorders are treated by over-the-counter or prescription hypnotic medications. Some of these medications, however, show prominent side effects, including sedation, memory problems, headaches, discontinuation insomnia, and sleepwalking, and may also become habit forming. Melatonin, a neurohormone secreted in a circadian fashion by the pineal gland, promotes sleep and regulates circadian rhythmicity by activating two membrane-bound G-protein coupled receptors in humans: the MT1 and MT2. Melatonin receptor agonists represent a new class of drugs indicated for the treatment of insomnia and circadian sleep disorders that are non-sedating and non- addictive, with ramelteon being the first nonselective MT1/MT2 melatonin receptor agonist marketed in the United States. Our goal is to design orally active, high affinity, and selective MT1 melatonin receptor agonists with optimal pharmacological, pharmacokinetic, and metabolic profiles to establish proof of concept and to further investigate the effectiveness of this series of compounds in promoting sleep and phase shifting altered circadian rhythms, while minimizing potential side effects due to persistent melatonin receptor desensitization/internalization. Towards these goals we will: 1) Develop computational strategies and chemical syntheses iteratively to identify novel chemical scaffolds (cores) and to improve ligand efficacy and selectivity for MT1 melatonin receptors, with subsequent selection of candidate molecules by a combination of in silico ligand-based discovery using phamacophores, virtual screening, and quantitative structure activity relationship and comparative molecular field analysis; 2) Determine ligand affinity, agonist potency, and receptor selectivity using [125I]-iodomelatonin binding to and stimulation of 35S-GTP- 3-S binding on hMT1 and hMT2 melatonin receptors expressed in mammalian cells; 3) Assess stability, brain penetration, and oral bioavailability of lead compounds; 4) Determine the functional efficacy of lead compounds on MT1 and/or MT2 melatonin receptors expressed in mouse suprachiasmatic nucleus (SCN) brain slices in vitro (i.e., inhibition of neuronal firing, phase shift of circadian rhythms of neuronal firing) and mouse in vivo models (i.e., phase shift activity rhythms onset). This collaborative project between Northwestern and Tougaloo researchers will merge expertise in medicinal chemistry, computational and structure-based drug discovery, and screening in in vitro and in vivo models to assess affinity, potency, and selectivity of lead compounds. Together, we will maximize opportunities for the discovery of much need research tools (i.e., MT1 selective ligands) and functionally active series of lead MT1 melatonin receptor agonists, with future potential for the treatment of insomnia and circadian sleep disorders, such as those observed in delayed sleep phase syndrome, blind individuals, and jet lag. PUBLIC HEALTH RELEVANCE: Sleep disorders due to stress, illness, chronic pain, psychiatric conditions, and poor sleep habits affect 70 million people in the United States, often leading to drowsiness, incoordination, and serious motor vehicle and other accidents. The goal of this proposal is to discover a drug that will mimic the effects of the hormone melatonin, which could be used to promote sleep and to treat sleep disorders caused by depression, Parkinson's disease, blindness, jet lag, shift work, and other related conditions.