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 神经生长因子依赖活性的分子增强剂及其作用机制的研究 在新的途径和细胞靶点方面促进神经元的分化和存活。这个 长期的目标是开发宝贵的工具，以更好地了解 活动增强和NGF在促进神经过程发育中的作用。已确定的线索 具有可接受的治疗方案的人将在SAR中取得进展，最终目标是开发治疗方案 预防或延缓由分子和化学缺陷引起的神经退行性变的药物 启动和维持轴突延伸的线索。本研究将利用以下方法 化学信息学和HTS用核心化学支架鉴定新结构和分子 与已知的NGF依赖轴突延伸的增强剂类似，天然产物来源于一种化学物质 小分子的图书馆。活性化合物的特征是效力、有效性、选择性和 在神经细胞谱系中识别先导化合物的特异性。黄连素作用机理的研究 将启动先导化合物以建立与已识别的相互作用的新途径和细胞靶点 线索。具有治疗价值的NGF增强剂的成功开发将产生巨大的影响 在改变与年龄相关的神经退行性疾病和其他痴呆症的结果方面。

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.