Stavrakov Georgi, Philipova Irena, Zheleva-Dimitrova Dimitrina, Valkova Iva, Salamanova Evdokiya, Konstantinov Spiro, Doytchinova Irini
Faculty of Pharmacy, Medical University of Sofia, Sofia, Bulgaria.
Institute of Organic Chemistry with Centre of Phytochemistry, Bulgarian Academy of Sciences, Sofia, Bulgaria.
Chem Biol Drug Des. 2017 Nov;90(5):709-718. doi: 10.1111/cbdd.12991. Epub 2017 May 12.
Galantamine (GAL) as an acetylcholinesterase inhibitor (AChEI) is among the main drugs approved for the treatment of Alzheimer's disease. It fits perfectly into acetylcholinesterase (AChE) binding gorge, but it is too short to fill it. The amyloid beta (Aβ) peptide binds in the peripheral anionic site (PAS) at the entrance of the binding gorge of AChE and initiates the formation of amyloid plaques. The blockade of PAS prevents from AChE-induced Aβ aggregation. In this study, we describe the design of a series of galantamine-camphane hybrids as AChEIs. Camphane (CAM) is a bulky fragment that disposes well on the wide gorge entrance. The designed hybrids have linkers of different length. They were docked into AChE, and the highest scored compounds were synthesized and tested for AChE inhibitory activity. Some of the novel hybrids showed 191- and 369-fold better inhibition than GAL. The CAM fragment of the best binders fits in the same region, proximal to PAS, where the Ω-loop of Aβ binds to AChE. The hybrids cross blood-brain barrier by passive diffusion and are non-neurotoxic at the inhibitory concentrations.
加兰他敏（GAL）作为一种乙酰胆碱酯酶抑制剂（AChEI），是被批准用于治疗阿尔茨海默病的主要药物之一。它能完美地契合乙酰胆碱酯酶（AChE）的结合通道，但长度太短无法填满该通道。淀粉样β蛋白（Aβ）肽结合在AChE结合通道入口处的外周阴离子位点（PAS），并引发淀粉样斑块的形成。对PAS的阻断可防止AChE诱导的Aβ聚集。在本研究中，我们描述了一系列作为AChEIs的加兰他敏 - 莰烷杂化物的设计。莰烷（CAM）是一个体积较大的片段，能很好地分布在宽阔的通道入口处。所设计的杂化物具有不同长度的连接子。将它们对接至AChE中，对得分最高的化合物进行合成，并测试其对AChE的抑制活性。一些新型杂化物的抑制作用比GAL分别强191倍和369倍。最佳结合物的CAM片段与Aβ的Ω环结合到AChE的同一区域，即靠近PAS的区域。这些杂化物通过被动扩散穿过血脑屏障，在抑制浓度下无神经毒性。
