Laboratori de Química Farmacèutica (Unitat Associada al CSIC), Facultat de Farmàcia, and Institut de Biomedicina (IBUB), Universitat de Barcelona, Av. Diagonal 643, 08028, Barcelona, Spain.
ChemMedChem. 2010 Nov 8;5(11):1855-70. doi: 10.1002/cmdc.201000322.
A new family of dual binding site acetylcholinesterase (AChE) inhibitors has been designed, synthesized, and tested for their ability to inhibit AChE, butyrylcholinesterase (BChE), AChE-induced and self-induced β-amyloid (Aβ) aggregation and β-secretase (BACE-1), and to cross the blood-brain barrier. The new heterodimers consist of a unit of racemic or enantiopure huprine Y or X and a donepezil-related 5,6-dimethoxy-2-[(4-piperidinyl)methyl]indane moiety as the active site and peripheral site to mid-gorge-interacting moieties, respectively, connected through a short oligomethylene linker. Molecular dynamics simulations and kinetics studies support the dual site binding to AChE. The new heterodimers are potent inhibitors of human AChE and moderately potent inhibitors of human BChE, AChE-induced and self-induced Aβ aggregation, and BACE-1, and are predicted to be able to enter the central nervous system (CNS), thus constituting promising multitarget anti-Alzheimer drug candidates with the potential to modify the natural course of this disease.
已经设计、合成了一类新的双结合位点乙酰胆碱酯酶（AChE）抑制剂，并对其抑制 AChE、丁酰胆碱酯酶（BChE）、AChE 诱导和自诱导β-淀粉样蛋白（Aβ）聚集以及β-分泌酶（BACE-1）的能力以及穿越血脑屏障的能力进行了测试。新的杂二聚体由一个手性或对映纯 huprine Y 或 X 单元和一个与多奈哌齐相关的 5,6-二甲氧基-2-[(4-哌啶基)甲基]茚满部分组成，分别作为活性部位和外周部位与中沟相互作用部分连接，通过短的寡亚甲基接头。分子动力学模拟和动力学研究支持 AChE 的双结合位点。这些新的杂二聚体是有效的人 AChE 抑制剂，对人 BChE、AChE 诱导和自诱导 Aβ 聚集以及 BACE-1 具有中度抑制作用，并预计能够进入中枢神经系统（CNS），因此构成了有前途的多靶点抗阿尔茨海默病药物候选物，有可能改变这种疾病的自然进程。
