二萜生物碱为乌头属和翠雀属植物特征化学成分，其中代表化合物甲基牛扁碱(MLA)具显著神经保护活性，被作为抗阿尔兹海默症的先导化合物，但毒性太大限制了其进一步研究。本申请基于前期从新疆特产空茎乌头中发现了新二萜生物碱空乌宁甲（ALA），该化合物具有新颖的侧链结构，其神经保护活性为MLA的5倍，而毒性仅为2%。初步的机制研究表明，ALA通过抑制乙酰胆碱酯酶活性，并诱导细胞保护性自噬，起到神经保护的作用，自噬也可能是其毒性大幅降低的主要原因。该发现突破了二萜生物碱抗阿尔兹海默症研究近20年的瓶颈。由此，本申请拟在经典药物设计理论指导下，通过亲缘植物活性成分的发现、ALA结构改造（母核修饰、孪药设计和侧链骨架跃迁）、活性筛选、毒性测试等研究，发现具神经保护活性的候选化合物，并结合蛋白质组学技术探究候选化合物的作用机制，为发现高效、低毒、机制清晰、靶标明确的二萜生物碱类抗阿尔兹海默症药物奠定基础。

Diterpenoid alkaloids are the main characteristic compounds in the genera of Aconitum and Delphinium. One of the representative compounds, Methyllycaconitine (MLA), reversibly binds and blocks nicotinic acetylcholine receptors (AchR) and has been identified as a potential lead for the treatment of Alzheimer’s disease. However, further studies on the therapeutic potential of MLA were hindered by its high toxicity. More recently, another neuroprotective diterpenoid alkaloids Apetalunine A (ALA) possessing special side chain from Aconitum apetalum, was found to be 5 times more potent than MLA while maintaining only 2% of its toxicity. Initial mechanistic studies revealed that ALA exhibited its neuroprotective effects by inhibiting the Acetylcholinesterase activity and inducing autophagic cell death. ALA-induced autophagy was also thought to be the main reason for the reduction of its toxicity, which is a breakthrough in the fight against Alzheimer's disease using diterpenoid alkaloids. Based on this, we plan to use classical drug design strategies, including screening of active compounds from related species, structural modifications of ALA (Core-modification, Twin drug design, and Side chain scaffold hopping), anti-AchR activity screening, toxicity testing, etc. to discover novel neuroprotective candidates. What’s more, the underlying mechanisms of the candidates could be explored using proteomics approaches to provide support for the development of better diterpenoid alkaloids-based anti-Alzheimer’s drugs with higher potency, fewer toxicity, clear mechanism and unambiguous target.