Identification of Small Molecule Ligands with NGF Potentiating Activity

本申请中描述的研究的具体目的是开发新的有效的和选择性的小分子化合物。 神经元中NGF依赖性活性的分子增强剂，并表征其作用机制 n促进神经元分化和存活的新途径和细胞靶点。的 长期目标是开发宝贵的工具，以更好地了解 活性增强和NGF在促进神经过程发育中的作用。已识别的电极导线 具有可接受的治疗特征的药物将通过SAR进展，最终目标是开发治疗 预防或延迟由分子和化学物质缺陷引起的神经变性发作的药物， 启动和维持神经突延伸的线索。本研究将利用以下方法 化学信息学和HTS，以确定具有核心化学支架的新结构和分子， 类似于已知NGF依赖性神经突延伸增强剂的天然产物来源于化学品 小分子文库。活性化合物将表征效力、功效、选择性和生物活性。 神经元细胞谱系中的特异性来鉴定先导化合物。作用机制的研究 先导化合物将被启动，以建立新的途径和细胞靶点， 线索.成功开发具有治疗价值的NGF增强剂将产生巨大的影响 改变与年龄相关的神经退行性疾病和其他痴呆症的结果。

The specific aims of the research described in this application is to develop novel potent and selective small molecule potentiators of NGF dependent activity in neurons, and to characterize their mechanisms of action n promoting neuronal differentiation and survival with regards to new pathways and cellular targets. The objectives in the long-term are to develop invaluable tools to better understand the general mechanisms of activity potentiation and the roles of NGF in fostering the development of neural processes. Identified leads with acceptable therapeutic profiles will progress through SAR with the ultimate goal to develop therapeutic agents that prevent or delay the onset of neurodegeneration caused by defects in molecular and chemical cues that initiate and sustain neurite extension. This research will utilize the approaches of chemoinformatics and HTS to identify novel structures and molecules with core chemical scaffolds that are similar to known potentiators of NGF-dependent neurite extension of natural products origin from a chemical library of small molecules. Active compounds will be characterized for potency, efficacy, selectivity, and specificity in neuronal cell lineages to identify lead compounds. Studies on the mechanism of actions of leads compounds will be initiated to establish novel pathways and cellular targets that interact with identified leads. Successful development of NGF potentiators with therapeutic values will have a tremendous impact in modifying the outcome of age-related neurodegenerative diseases and other dementias.