Neurovascular Research Group, Instituto Cajal (CSIC), Ave. Doctor Arce 37, 28002 Madrid, Spain.
Experimental Neurology Unit, Center for Biomedical Technology (CTB), Universidad Politécnica de Madrid, Campus de Montegancedo S/N, Pozuelo de Alarcón, 28223 Madrid, Spain.
Int J Mol Sci. 2023 Jul 31;24(15):12254. doi: 10.3390/ijms241512254.
Great effort has been devoted to the synthesis of novel multi-target directed tacrine derivatives in the search of new treatments for Alzheimer's disease (AD). Herein we describe the proof of concept of MBA121, a compound designed as a tacrine-ferulic acid hybrid, and its potential use in the therapy of AD. MBA121 shows good -amyloid (A) anti-aggregation properties, selective inhibition of human butyrylcholinesterase, good neuroprotection against toxic insults, such as A, A, and HO, and promising ADMET properties that support translational developments. A passive avoidance task in mice with experimentally induced amnesia was carried out, MBA121 being able to significantly decrease scopolamine-induced learning deficits. In addition, MBA121 reduced the A plaque burden in the cerebral cortex and hippocampus in APP/PS1 transgenic male mice. Our in vivo results relate its bioavailability with the therapeutic response, demonstrating that MBA121 is a promising agent to treat the cognitive decline and neurodegeneration underlying AD.
研究人员投入了大量精力，合成新型多靶点导向他克林衍生物，以期寻找阿尔茨海默病（AD）的新疗法。本文介绍了 MBA121 的概念验证，它是一种设计为他克林-阿魏酸杂合体的化合物，有望用于 AD 的治疗。MBA121 具有良好的β淀粉样蛋白（A）聚集抑制作用，对人丁酰胆碱酯酶具有选择性抑制作用，对 A、A 和 HO 等有毒物质的神经毒性具有良好的保护作用，并且具有良好的 ADMET 特性，支持转化发展。在实验性诱导记忆障碍的小鼠中进行了被动回避任务，结果表明 MBA121 能显著降低东莨菪碱诱导的学习障碍。此外，MBA121 还降低了 APP/PS1 转基因雄性小鼠大脑皮层和海马中的 A 斑块负担。我们的体内研究结果将其生物利用度与治疗反应相关联，表明 MBA121 是一种有前途的治疗 AD 认知能力下降和神经退行性变的药物。
