Abstract

Effective therapy of Alzheimer’s disease (AD) requires treatment with a combination of drugs that modulate various pathomechanisms contributing to the disease. In our research, we have focused on the development of multi-target-directed ligands – 5-HT₆ receptor antagonists and cholinesterase inhibitors – with disease-modifying properties. We have performed extended in vitro (FRET assay) and in cellulo (Escherichia coli model of protein aggregation) studies on their β-secretase, tau, and amyloid β aggregation inhibitory activity. Within these multifunctional ligands, we have identified compound 17 with inhibitory potency against tau and amyloid β aggregation in in cellulo assay of 59% and 56% at 10 µM, respectively, hBACE IC₅₀=4 µM, h5TH6 K _i=94 nM, hAChE IC₅₀=26 nM, and eqBuChE IC₅₀=5 nM. This study led to the development of multifunctional ligands with a broad range of biological activities crucial not only for the symptomatic but also for the disease-modifying treatment of AD.

摘要

有效的阿尔茨海默氏病（AD）疗法需要使用能够调节导致该病的各种病理机制的药物组合进行治疗。在我们的研究中，我们专注于开发具有疾病调节特性的多靶标定向配体– 5-HT ₆受体拮抗剂和胆碱酯酶抑制剂。我们已经对它们的β-分泌酶，tau和淀粉样蛋白β聚集抑制活性进行了扩展的体外（FRET分析）和纤维素（大肠埃希氏大肠杆菌蛋白质聚集模型）研究。在这些多功能配体，我们已经确定的化合物17与对tau蛋白和β淀粉样蛋白聚集的抑制效力于纤维素的分别在10 µM下检测59％和56％，h BACE IC ₅₀ = 4 µM，h 5TH6 K _i = 94 nM，h AChE IC ₅₀ = 26 nM，eq BuChE IC ₅₀ = 5 nM。这项研究导致开发了具有广泛生物学活性的多功能配体，这些活性不仅对AD的症状缓解，而且对改善疾病的治疗也至关重要。