阿尔茨海默症是一种以记忆力损害和认知障碍为主的神经退行性疾病，严重影响患者的生活质量且发病率呈逐年递增。现有应用于临床的抗阿尔兹海默症药并不能遏制或逆转阿尔兹海默症病理改变。nAChR受体被认为是治疗阿尔兹海默症的潜在靶点。本项目以AchBP蛋白作为替代nAChR的研究工具，通过建立放射性同位素标记法测定化合物的AChBP结合活性，对自有化合物库进行初步的活性筛选，并得到活性与阳性药尼古丁相当的取代哌啶类化合物SLL-73 (IC50=95.4 nM)。依据合理设计思想，结合结构生物学和计算机分子模拟，进行取代哌啶类分子的设计、合成与再设计。在体外活性优化的同时，运用成药性体外评价指标考察其成药性变化。在体外评价基础上，采用动物模型测定候选化合物的血脑屏障穿透性和体内抗阿尔兹海默活性。

As a neurodegenerative disease, Alzheimer's disease (AD) is characterized by memory loss and cognitive disorder with increasing prevalence and social burden. Current treatments in clinical situations failed to reverse or even suppress the pathological changes of AD. Drugs targeting N-acetylcholine receptor (nAChR) have been considered to be potential treatments for AD. In our previous works, a acetylcholine binding protein (AChBP) based model was established and validated to screen for compound with potential nAChR activities. SLL-73 (IC50=95.4 nM) was identified as a hit with AChBP binding activities from novel substituted piperidine derivatives similar to nicotine. In this program, starting from the knowledge of current results, in combination with findings of structural biology and molecular modeling, a series of compounds will be designed and synthesized to afford novel piperidine derivatives. The developability of hits will be examined further. Following the in vitro tests as well as the druggability evaluations, we will further investigate the blood-brain penetration and in vivo efficacy for the lead compounds.