脑源性神经生长因子可通过刺激神经元的再生恢复神经回路，从而改善阿尔茨海默症(AD)模型动物的学习和记忆功能，为AD的治疗提供了新方向，但因其化学性质不稳定和不易通过血脑屏障等缺陷限制了其临床应用。因此，研发可促进神经新生和分化的小分子药物先导物具有重要的临床意义。前期工作中，我们首次发现部分C-15位取代的一叶萩碱型生物碱具有良好的促神经分化和突触形成活性，并发现该类化合物可促进神经细胞中蛋白质的合成，以及诱导ERK和Akt蛋白的磷酸化水平升高，但其具体的构效关系和作用机制尚不清楚。本项目拟在前期工作基础上，设计合成系列C-15位连有不同取代基团的一叶萩碱型生物碱衍生物，并对其促神经细胞分化活性进行评价及开展构效关系研究；此外，还将通过分子生物学方法并结合小分子探针技术，对该类化合物促神经分化活性的作用机制及其作用靶标进行研究，为研发新型的抗AD药物提供科学依据。

Alzheimer’s disease (AD) has become an urgent threat to public health with the acceleration of global population aging. Because our understanding of the pathogenesis of AD is limited, there is no effective therapeutic drug for the treatment of AD. Recent studies have demonstrated that brain-derived neurotrophic factor (BDNF) can stimulate adult neurogenesis, and in turn restore hippocampal circuit to improve the learning and memory of AD model animals. These findings provide a new strategy for the treatment of AD. However, due to its chemical instability and permeability of blood-brain barrier, the clinical application of BDNF is still unsuccessful. Therefore, it is of great significance to discover and develop new small-molecule drug leads with neurogenesis and neural differentiation promoting activities. In our previous investigation, we demonstrated for the first time that several C-15 substituted securinine-type alkaloids showed significant activity in promoting neuronal differentiation of Neuro-2a cells. Preliminary molecular mechanism studies of selected active alkaloids showed that general mRNA translation was activated and Akt and ERK dependent pathways are upregulated in Neuro-2a cells, which may attribute to the neuronal differentiation activities of these compounds. However, structure-activity relationship and action mechanism of these compounds remain unknown. Based on the previous study, in this project, we are planning to design and synthesize a compound library of C-15 substituted securinine-type alkaloid derivatives. Furthermore, the neuronal differentiation activity of these compounds, as well as their structure-activity relationship and action mechanism will also be investigated. Our findings could be used as scientific evidence for the new drug development for the treatment of AD.