Faculty of Pharmacy , University of Ljubljana , Askerceva 7 , 1000 Ljubljana , Slovenia.
Department of Toxicology and Military Pharmacy , Faculty of Military Health Sciences , Trebesska 1575 , 500 01 Hradec Kralove , Czech Republic.
ACS Chem Neurosci. 2018 May 16;9(5):1195-1214. doi: 10.1021/acschemneuro.8b00024. Epub 2018 Feb 13.
Alzheimer's disease (AD) is a major public health problem, which is due to its increasing prevalence and lack of effective therapy or diagnostics. The complexity of the AD pathomechanism requires complex treatment, e.g. multifunctional ligands targeting both the causes and symptoms of the disease. Here, we present new multitarget-directed ligands combining pharmacophore fragments that provide a blockade of serotonin 5-HT receptors, acetyl/butyrylcholinesterase inhibition, and amyloid β antiaggregation activity. Compound 12 has displayed balanced activity as an antagonist of 5-HT receptors ( K = 18 nM) and noncompetitive inhibitor of cholinesterases (IC = 14 nM, IC = 22 nM). In further in vitro studies, compound 12 has shown amyloid β antiaggregation activity (IC = 1.27 μM) and ability to permeate through the blood-brain barrier. The presented findings may provide an excellent starting point for further studies and facilitate efforts to develop new effective anti-AD therapy.
阿尔茨海默病（AD）是一个主要的公共卫生问题，这是由于其发病率的增加和缺乏有效的治疗或诊断方法。AD 发病机制的复杂性需要复杂的治疗方法，例如针对疾病的原因和症状的多功能配体。在这里，我们提出了新的多靶点导向配体，结合了提供 5-羟色胺 5-HT 受体阻断、乙酰/丁酰胆碱酯酶抑制和淀粉样β抗聚集活性的药效团片段。化合物 12 作为 5-HT 受体拮抗剂（K = 18 nM）和胆碱酯酶非竞争性抑制剂（IC = 14 nM，IC = 22 nM）具有平衡的活性。在进一步的体外研究中，化合物 12 显示出淀粉样β抗聚集活性（IC = 1.27 μM）和穿透血脑屏障的能力。所提出的研究结果可能为进一步的研究提供一个极好的起点，并有助于开发新的有效的抗 AD 治疗方法。
