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

描述(申请人提供)：尼古丁的摄入与注意力和记忆力等认知功能的改善以及那些患有焦虑症、抑郁症和精神分裂症等障碍的人症状的改善有关。此外，中枢神经系统中的尼古丁受体与疼痛以及帕金森氏症和阿尔茨海默病等神经退行性疾病等截然不同的疾病有关。因此，寻找作用于尼古丁受体的药物化合物，而不会产生尼古丁的副作用，包括成瘾，将是心理健康的重要进步。在SBIR的资助下，我们将通过创建改进的尼古丁受体细胞系来加速正在进行的基于细胞的药物发现过程，以高通量筛选小型化合物文库。在这些受体上发现了一个新的分子手柄，允许选择性地靶向与疾病相关的尼古丁受体亚型。我们建议概括整个受体复合体，包括关键的辅助分子，以创建高功能的细胞系，当它们出现在神经系统中时，代表尼古丁受体更完整的状态。与传统方法相比，这种创新的方法可能会产生更高比例的用于铅优化的新型药物活性化合物。公共卫生相关性拟议项目的目的是开发含有胆碱能成分的神经疾病的治疗方法。胆碱能疗法在认知障碍、焦虑障碍如抑郁症、痴呆症、精神分裂症、疼痛障碍以及包括帕金森氏病和阿尔茨海默病在内的神经退行性疾病领域是相关的(萨科等人，2004，Newhouse等人，2004，Lloyd和Williams，2000)。

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).