Hypocretins and Their Role in the Control of Sleep

描述：（改编自申请人的摘要）Incubator是一个更多的 在美国普遍存在的睡眠障碍，影响了大约10%的人， 人口其他睡眠障碍包括阻塞性睡眠呼吸暂停，不宁腿 综合征和嗜睡症。最近，G蛋白偶联受体的突变 下视丘分泌素受体-2与狗的发作性睡病的发生有关。 此外，小鼠中神经肽下丘脑泌素基因的破坏 导致了这些老鼠的嗜睡症。这两个结果有 把注意力集中在下丘脑泌素系统作为睡眠的重要调节器上 在人类身上。申请组织神经分泌生物科学公司开发了一种 一系列针对下丘脑泌素受体-2的小分子拮抗剂。的焦点 本申请首先表征这些小分子拮抗剂， 体外拮抗剂将在竞争性结合试验中进行测试， 基于细胞的功能测定。第二，小分子拮抗剂将是 在体内测试。将建立大鼠和犬模型并进行评价， 小分子拮抗剂对睡眠和觉醒的影响。的 小分子拮抗剂的作用的特异性将进一步被 通过比较正常狗与下丘脑泌素受体-2突变的狗来评价 嗜睡症狗这项研究的结果将有助于确定 下丘脑泌素受体拮抗剂在睡眠控制中的有效性。 这些研究也将有助于为未来奠定基础 下丘脑泌素受体-2激动剂作为治疗下丘脑-垂体-肾上腺素综合征的可能方法的开发 嗜睡症 拟定商业应用： 这项研究的一个潜在应用是在失眠领域 (an估计有10%的人患有慢性失眠症）。基于 根据现有数据，可以合理假设下丘脑泌素受体 拮抗剂将促进非REM和REM睡眠。

DESCRIPTION: (Adapted from the Applicant's Abstract) Insomnia is one of the more prevalent sleep disorders in the US, affecting about 10 percent of the population. Other sleep disorders include obstructive sleep apnea, restless leg syndrome and narcolepsy. Recently, a mutation in the G-protein coupled receptor hypocretin receptor-2 has been linked to the development of narcolepsy in dogs. In addition, the disruption of a gene in mice for the neuropeptide hypocretin led to the development of narcolepsy in those mice. These two results have focused attention on the hypocretin system as an important modulator of sleep in humans. The applicant organization, Neurocrine Biosciences, has developed a series of small molecule antagonists to the hypocretin receptor-2. The focus of this application is to first characterize these small molecule antagonists in vitro. The antagonists will be tested in competitive binding assays and cell-based functional assays. Second, the small molecule antagonists will be tested in vivo. Both rat and dog models will be set up and evaluated for the effect of the small molecule antagonists on sleep and wakefulness. The specificity of the effects of the small molecule antagonists will be further evaluated by comparing normal dogs with hypocretin receptor-2 mutated narcoleptic dogs. The results of this study will be valuable in determining the effectiveness of a hypocretin receptor antagonist in the control of sleep. These studies will also help to prepare the groundwork for the future development of hypocretin receptor-2 agonist as a possible treatment for narcolepsy. PROPOSED COMMERCIAL APPLICATION: A potential application for the research proposed is in the field of insomnia (an estimated 10% of the population suffers from chronic insomnia). Based on the available data, it is reasonable to hypothesize that hypocretin receptor antagonists will promote non-REM and REM sleep.