Improved Cell Line and Assay Development of Nicotinic Receptor Complexes for HTS

描述（由申请人提供）：尼古丁消费与改善认知功能（如注意力和记忆力）以及改善焦虑、抑郁和精神分裂症等疾病患者的症状有关。此外，中枢神经系统中的尼古丁受体与疼痛、帕金森氏症和阿尔茨海默氏症等神经退行性疾病等完全不同的疾病有关。因此，找到既能作用于尼古丁受体，又不会产生尼古丁上瘾等副作用的药物化合物，将是精神健康领域的重要进展。在SBIR的资助下，我们将通过创建用于小化合物文库高通量筛选的改进的烟碱受体细胞系来加速正在进行的基于细胞的药物发现过程。这些受体的新分子手柄的发现，允许选择性靶向与疾病有关的烟碱受体亚型。我们建议概括整个受体复合体，包括创造高功能细胞系的关键辅助分子，这些细胞系代表了尼古丁受体在神经系统中更完整的状态。与传统方法相比，这种创新方法可能产生更高百分比的用于先导优化的新型药物活性化合物。拟议项目的目的是开发具有胆碱能成分的神经系统疾病的治疗方法。胆碱能疗法与认知障碍、焦虑障碍（如抑郁症、痴呆、精神分裂症）、疼痛障碍和神经退行性疾病（包括帕金森病和阿尔茨海默病）等领域相关（萨科等人，2004年，纽豪斯等人，2004年，劳埃德和威廉姆斯，2000年）。

DESCRIPTION (provided by applicant): Nicotine consumption is linked to improvements in cognitive functions such as attention and memory, as well as improvements in symptoms for those suffering from disorders such as anxiety, depression and schizophrenia. Furthermore, nicotinic receptors in the central nervous system have been implicated in such wildly disparate conditions such as pain and neurodegenerative disorders like Parkinson's and Alzheimer's disease. Therefore, finding pharmaceutical compounds, which act on nicotinic receptors, without the side effects of nicotine including addiction, would constitute an important advancement for mental health. With SBIR funding, we will accelerate the ongoing cell- based drug discovery process by creating improved nicotinic receptor cell lines for high throughput screening of small compound libraries. The discovery of a novel molecular handle on these receptors, allows for the selective targeting of nicotinic receptor subtypes involved in disease. We propose to recapitulate the entire receptor complex including key accessory molecules in creating high functioning cell lines that represent a more complete state of nicotinic receptors as they occur in the nervous system. This innovative approach is likely to yield a higher percentage of novel classes of pharmaceutically active compounds for lead optimization than those obtained with traditional methods. PUBLIC HEALTH RELEVANCE The aim of the proposed project is for the development of therapeutic treatments of neurological disorders with a cholinergic component. Cholinergic therapeutics are relevant in the area of cognitive disorders, anxiety disorders such as depression, dementias, schizophrenia, in pain disorders, and neurodegenerative disorders including Parkinson's disease and Alzheimer's disease (Sacco et al., 2004, Newhouse et al., 2004, Lloyd and Williams, 2000).