治疗阿尔茨海默病的乙酰胆碱酯酶抑制剂的分子设计：从多位点抑制剂到一药多靶  

Design of acetylcholinesterase inhibitor for Alzheimer's disease therapy:from multi-binding site inhibitors to multi-target directed ligands

作　　者：杨文超 孙琦 喻宁熙 朱晓磊 杨光富 

机构地区：[1]农药与化学生物学教育部重点实验室,华中师范大学化学学院,湖北武汉430079

出　　处：《药学学报》2012年第3期313-321,258,共9页Acta Pharmaceutica Sinica

基　　金：国家自然科学基金资助项目(20902034)

摘　　要：阿尔茨海默病(Alzheimer's disease,AD)是一种病因尚不明确且致病机制极为复杂的神经退行性疾病,严重威胁老年人的健康并对整个社会发展带来沉重的负担。设计开发治疗阿尔茨海默病的药物一直是药物研发领域的热点和难点,其中尤以乙酰胆碱酯酶(acetylcholinesterase,AChE)抑制剂的研究最为活跃并已在临床中成功应用。然而,现有商品化AChE抑制剂的临床治疗效果有限,并且都伴随不同程度的毒副作用。因此,寻找高效、低毒的多重结合位点的AChE抑制剂和针对多重作用靶标的多功能抑制剂(即一药多靶)成为AChE抑制剂分子设计的主要发展方向。本文结合近年来的研究进展,从代表性AChE抑制剂的化学结构和结合模式出发,对AChE抑制剂分子设计的发展历程及最新成果进行了综述。Alzheimer＇s disease（AD） is a complex neurodegenerative disorder which seriously causes the dementia in elderly people and afflicts millions of people worldwide.Drug discovery for Alzheimer＇s disease therapy has been a hot research area and a big challenge,in which development of acetylcholinesterase（AChE） inhibitors design was the most active and some AChE inhibitors are commercially available for AD medication already.However,practical using of commercial AChE inhibitors showed their limited usefulness and related adverse effects.Thus,it is extremely urgent to find novel AChE inhibitors with higher potency and less adverse effects.Based on the accurate crystallographic studies about AChE,strategies for multi-binding site AChE inhibitors have been formed,followed by design of the multi-target directed ligands.In this review,the structures and binding modes of commercial AChE inhibitors were briefly discussed,together with the development of AChE inhibitor design for AD therapy：from multi-binding site inhibitors to multi-target directed ligands.

关 键 词：阿尔茨海默病 乙酰胆碱酯酶抑制剂 多位点抑制剂 一药多靶 分子设计 

分 类 号：R916[医药卫生—药学]