双位点作用的乙酰胆碱酯酶抑制剂  

Dual Binding Site Acetylcholinesterase Inhibitors

作　　者：郑伟[1,2] 谢琼[3] 陈良康[1,2] 陈建兴[1,2] 仇缀百[3] 

机构地区：[1]上海市计划生育科学研究所国家人口计生委重点实验室,上海200032 [2]上海生殖健康药具工程技术研究中心,上海200032 [3]复旦大学药学院,上海201203

出　　处：《化学进展》2013年第11期1973-1980,共8页Progress in Chemistry

基　　金：国家自然科学基金项目(No.21202098);上海市晨光计划项目(No.10CG03)资助

摘　　要：阿尔茨海默病(AD)是一种严重威胁老年人生命健康的疾病,在针对不同靶点的抗AD药物开发中,基于双位点作用的乙酰胆碱酯酶抑制剂的研究是当前热点领域。这类抑制剂不仅能提高患者脑内乙酰胆碱水平以改善其认知能力,同时可干扰Aβ的聚集,调控病理过程,从而发挥双重治疗AD的作用。本文综述了双位点作用的乙酰胆碱酯酶抑制剂的作用机理及近几年来已报道的先导化合物,同时结合本课题组开发的左旋美普他酚类双配基的研究结果,总结此类化合物的合理设计和构效关系,对双位点作用的乙酰胆碱酯酶抑制剂的药物开发中面临的一些挑战进行探讨,并对其发展趋势作了展望。Alzheimer＇s disease （AD） is becoming a serious threat to life expectancy for elderly people. A hot area of treatments for AD is to develop dual binding site acetylcholinesterase （AChE） inhibitors that simultaneously interact with both the catalytic and peripheral anionic sites of the enzyme. These compounds may act as disease-modifying agents with multiple functions, not only improving cognition of AD patients by elevating acetylcholine levels, but also interfering with β-amyloid （Aβ） aggregation and delaying Aβ-elicited pathological process. Thus, the novel promising dual binding site AChE inhibitors reported in recent years are the focus of this review. Here, we first introduce the action mechanism of dual binding site AChE inhibitors, and then summarize the main classes of dimeric or hybrid compounds, along with the pharmacological profile of the most active candidates for AD therapy. In addition, combined with our preceding studies on （-）-meptazinol-based bivalents, the rational design strategy and structure-activity relationship of dual binding site AChE inhibitors are discussed. The current challenges and development trends are also proposed.

关 键 词：阿尔茨海默病 候选药物 双位点作用 乙酰胆碱酯酶抑制剂 Aβ聚集 

分 类 号：O62[理学—有机化学] Q556.1[理学—化学]