Highly Potent and Selective Butyrylcholinesterase Inhibitors for Cognitive Improvement and Neuroprotection
Qi Li, Ying Chen, Ying Chen, Shuaishuai Xing, Qinghong Liao, Baichen Xiong, Yuanyuan Wang, Weixuan Lu, Siyu He, Feng Feng, Wenyuan Liu, Yao Chen, Yao Chen, Haopeng Sun
Abstract
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 S06-1011 (hBChE IC50 = 16 nM) and S06-1031 (hBChE IC50 = 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 Aβ1–42 peptide-induced cognitive deficit models. The best candidate S06-1011 increased the level of ghrelin, a substrate of BChE, which can function as improving the mental mood appetite. The weight gain of the S06-1011-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.