石杉碱甲-他克林异二聚体的合成与药理学评价：亚纳摩尔双结合位点乙酰胆碱酯酶抑制剂

Synthesis and pharmacological evaluation of huprine-tacrine heterodimers: subnanomolar dual binding site acetylcholinesterase inhibitors.

作者信息

Camps Pelayo, Formosa Xavier, Muñoz-Torrero Diego, Petrignet Julien, Badia Albert, Clos M Victoria

机构信息

Laboratori de Química Farmacèutica, Facultat de Farmàcia, Universitat de Barcelona, Av. Diagonal 643, E-08028, Barcelona, Spain.

出版信息

J Med Chem. 2005 Mar 24;48(6):1701-4. doi: 10.1021/jm0496741.

DOI:10.1021/jm0496741

PMID:15771413

Abstract

A series of huprine-tacrine heterodimers has been developed by connection of huprine Y, a compound with one of the highest affinities for the active site of acetylcholinesterase yet reported, with tacrine, a compound with known affinity for the peripheral site of the enzyme, through a linker of appropriate length to allow simultaneous interaction with both binding sites. These compounds exhibit human acetylcholinesterase and butyrylcholinesterase inhibitory activities with IC(50) values in the subnanomolar and low nanomolar range, respectively.

摘要

通过连接石杉碱Y（一种据报道对乙酰胆碱酯酶活性位点具有最高亲和力之一的化合物）和他克林（一种对该酶外周位点具有已知亲和力的化合物），借助适当长度的连接子以实现与两个结合位点同时相互作用，从而开发出了一系列石杉碱 - 他克林异二聚体。这些化合物分别表现出对人乙酰胆碱酯酶和丁酰胆碱酯酶的抑制活性，其IC(50)值分别在亚纳摩尔和低纳摩尔范围内。