阿尔茨海默病（AD）危害巨大，发病机制复杂，目前尚无有效治疗药物。申请人前期对宁夏枸杞的果实（中药枸杞子）抗AD活性成分进行了深入研究，首次从活性部位中发现了一类结构全新、主含、特征性的、具有抗AD活性的二咖啡酰亚精胺类衍生物，命名为“枸杞亚精胺”。文献调研表明，宁夏枸杞的根皮（中药地骨皮）以及同属药用植物黑果枸杞中存在大量枸杞亚精胺的类似物，值得深入研究。本项目拟在建立枸杞亚精胺及类似物快速检识方法基础上，从地骨皮和黑果枸杞中靶向分离获得枸杞亚精胺类似物；采用转基因AD果蝇、神经细胞等实验，评价其抗AD活性，探讨构效关系；同时综合考虑计算机辅助的ADME成药性质预测及化合物富集方法等信息，优选出枸杞亚精胺类抗AD候选分子，开展其克级样品富集和转基因AD小鼠药效评价；并探索其抗AD作用机制和靶点，以期获得机制明确的枸杞亚精胺类抗AD候选药物，为天然来源抗AD新药研制奠定基础。

Alzheimer’s disease (AD) is a tremendous threat to global public health, and there are no curative therapies currently available for this disease, the pathogenesis of which is complicated. In applicant’s previous research on the anti-AD active constituents of the fruit of Lycium barbarum (wolfberry), a series of new, major, characteristic, and anti-AD active dicaffeoylspermidine derivatives, named "lycibarbarspermidines", were firstly isolated from the anti-AD active fraction of wolfberry. The previous papers showed that a variety of analogues of lycibarbarspermidines were existed in the root bark of Lycium barbarum (jikoppi) and Lycium ruthenicum, respectively. Based on the above research, the strategy of rapid charaterization of lycibarbarspermidines and its analogues will be established for the isolation of its analogues from jikoppi and Lycium ruthenicum. Then, the structure—anti-AD activity relationship (SAR) of lycibarbarspermidines and its analogues will be discussed based on the data from the transgenic fly AD model and primary rat cortical neuron assay. Based on SAR, computer-aided druggability prediction of ADME, and the enrichment method of compounds, the anti-AD candidate compounds of lycibarbarspermidines and its anologues will be optimal selected, followed by the enrichment of the candidate compounds. The transgenic mice AD model will be applied to confirm the anti-AD activity and explore anti-AD mechanism of the candidate compounds, and ligand-receptor capture technology will be carried out to search the potential targets of the candidate compounds. In conclusion, this project is to optimally select the anti-AD candidate drugs of lycibarbarspermidines and its analogues with the explicit mechanism for the research of anti-AD new drugs derived from nature.