Li Qi, Chen Ying, Xing Shuaishuai, Liao Qinghong, Xiong Baichen, Wang Yuanyuan, Lu Weixuan, He Siyu, Feng Feng, Liu Wenyuan, Chen Yao, Sun Haopeng
School of Pharmacy, China Pharmaceutical University, Nanjing 211198, People's Republic of China.
School of Basic Medicine, Qingdao University, Qingdao 266071, People's Republic of China.
J Med Chem. 2021 May 27;64(10):6856-6876. doi: 10.1021/acs.jmedchem.1c00167. Epub 2021 May 11.
Butyrylcholinesterase (BChE) has been considered as a potential therapeutic target for Alzheimer's disease (AD) because of its compensation capacity to hydrolyze acetylcholine (ACh) and its close association with Aβ deposit. Here, we identified (BChE IC = 16 nM) and (BChE IC = 25 nM) as highly effective and selective BChE inhibitors, which were proved to be safe and long-acting. Candidate compounds exhibited neuroprotective effects and the ability to improve cognition in scopolamine- and Aβ peptide-induced cognitive deficit models. The best candidate increased the level of ghrelin, a substrate of BChE, which can function as improving the mental mood appetite. The weight gain of the -treated group remarkably increased. Hence, BChE inhibition not only plays a protective role against dementia but also exerts a great effect on treating and nursing care.
由于丁酰胆碱酯酶（BChE）具有水解乙酰胆碱（ACh）的代偿能力及其与β淀粉样蛋白（Aβ）沉积的密切关联，它一直被视为阿尔茨海默病（AD）的一个潜在治疗靶点。在此，我们鉴定出[具体化合物1]（BChE IC50 = 16 nM）和[具体化合物2]（BChE IC50 = 25 nM）为高效且选择性的BChE抑制剂，已证明它们安全且长效。候选化合物在东莨菪碱和Aβ肽诱导的认知缺陷模型中表现出神经保护作用以及改善认知的能力。最佳候选物[具体化合物]提高了BChE的一种底物——胃饥饿素的水平，胃饥饿素可起到改善精神情绪和食欲的作用。[具体化合物]治疗组的体重显著增加。因此，抑制BChE不仅对痴呆症起到保护作用，而且在治疗和护理方面也发挥着巨大作用。
