Huprine-Tacrine Heterodimers as Anti-Amyloidogenic Compounds of Potential Interest against Alzheimer's and Prion Diseases
Huprine-Tacrine Heterodimers as Anti-Amyloidogenic Compounds of Potential Interest against Alzheimer's and Prion Diseases
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DOI：
10.1021/jm200840c
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发表时间：
2012-01-26
影响因子：
7.3
通讯作者：
Munoz-Torrero, Diego
中科院分区：
文献类型：
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作者：
Galdeano, Caries;Viayna, Elisabet;Munoz-Torrero, Diego
一个家族的石杉碱-他克林异源二聚体已被开发，同时阻断活性和外周位点的乙酰胆碱酯酶（AChE）。动力学和分子模拟研究支持其对AChE的双位点结合，导致对人AChE的催化活性的高度有效的抑制，并且更重要的是，在体外中和AChE对β-淀粉样肽（A β）和朊病毒肽两者的聚集的病理性陪伴作用，所述朊病毒肽在π蛋白的聚集中具有关键作用。石杉碱-他克林异二聚体具有附加价值，因为它们对人丁酰胆碱酯酶、自诱导A β聚集和β-分泌酶显示出有效的体外抑制活性。最后，它们能够穿过血脑屏障，正如在人工膜模型测定中预测的那样，并在OF 1小鼠的离体实验中证明，到达中枢神经系统中的多个生物靶点。总体而言，这些化合物是用于治疗阿尔茨海默病和朊病毒疾病的有希望的先导化合物。
A family of huprine-tacrine heterodimers has been developed to simultaneously block the active and peripheral sites of acetylcholinesterase (AChE). Their dual site binding for AChE, supported by kinetic and molecular modeling studies, results in a highly potent inhibition of the catalytic activity of human AChE and, more importantly, in the in vitro neutralization of the pathological chaperoning effect of AChE toward the aggregation of both the beta-amyloid peptide (A beta) and a prion peptide with a key role in the aggregation of the pion protein. Huprine-tacrine heterodimers take on added value in that they display a potent in vitro inhibitory activity toward human butyrylcholinesterase, self-induced A beta aggregation, and beta-secretase. Finally, they are able to cross the blood-brain barrier, as predicted in an artificial membrane model assay and demonstrated in ex vivo experiments with OF1 mice, reaching their multiple biological targets in the central nervous system. Overall, these compounds are promising lead compounds for the treatment of Alzheimer's and prion diseases.