Tacrine(10)-hupyridone, a dual-binding acetylcholinesterase inhibitor, potently attenuates scopolamine-induced impairments of cognition in mice
Tacrine(10)-hupyridone (A10E) was designed as a dual-binding acetylcholinesterase (AChE) inhibitor from the modification of tacrine and a fragment of huperzine A. We have found that A10E effectively inhibited AChE in a mixed competitive manner, with an IC50 of 26.4 nM, which is more potent than those of tacrine and huperzine A. Most importantly, we have shown, for the first time that A10E attenuated scopolamine-induced cognitive impairments without affecting motor function in mice. A10E effectively attenuated impairments of learning and memory to a similar extent as donepezil, an inhibitor of AChE used for treating Alzheimer’s disease (AD). In addition, A10E significantly decreased AChE activity in the brain of mice, suggesting that A10E might cross the brain blood-barrier. Taken together, our results demonstrated that A10E, a designed dual-binding AChE inhibitor, could effectively reverse cognitive impairments, indicating that A10E might provide therapeutic efficacy for AD treatment.
KeywordsTacrine(10)-hupyridone Acetylcholinesterase Alzheimer’s disease Scopolamine Dual-binding
central anion site
peripheral anion site
This work was supported by National Natural Science Foundation of China (81673407, U1503223), Applied Research Project on Nonprofit Technology of Zhejiang Province (2016C37110), Ningbo international science and technology cooperation project (2014D10019), Ningbo municipal innovation team of life science and health (2015C110026), Guangdong Provincial International Cooperation Project of Science & Technology (2013B051000038), Shenzhen Basic Research Program (JCYJ20160331141459373), Guangdong-Hong Kong Technology Cooperation Funding Scheme (GHP/012/16GD), Research Grants Council of Hong Kong (15101014), Hong Kong Polytechnic University (G-YBGQ, G-YZ95), LiDakSum Marine Biopharmaceutical Development Fund, and the K. C. Wong Magna Fund in Ningbo University. We sincerely thank Prof. Paul R Carlier to provide A10E.
Compliance with ethical standards
Conflict of interest
The authors declare no competing financial interests.
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