【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。更多还原

【Abstract】 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 diseasemodifying 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.更多还原