Metabolic Brain Disease

, Volume 33, Issue 4, pp 1131–1139 | Cite as

Tacrine(10)-hupyridone, a dual-binding acetylcholinesterase inhibitor, potently attenuates scopolamine-induced impairments of cognition in mice

  • Huixin Chen
  • Siying Xiang
  • Ling Huang
  • Jiajia Lin
  • Shengquan Hu
  • Shing-Hung Mak
  • Chuang Wang
  • Qinwen Wang
  • Wei Cui
  • Yifan Han
Original Article


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.


Tacrine(10)-hupyridone Acetylcholinesterase Alzheimer’s disease Scopolamine Dual-binding 







Alzheimer’s disease


acetylthiocholine iodide


central anion site


peripheral anion site


dithiobisnitrobenzoic acid



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.


  1. Anand P, Singh B (2013) A review on cholinesterase inhibitors for Alzheimer's disease. Arch Pharm Res 36:375–399CrossRefPubMedGoogle Scholar
  2. Bajda M, Guzior N, Ignasik M, Malawska B (2011) Multi-target-directed ligands in Alzheimer's disease treatment. Curr Med Chem 18:4949–4975CrossRefPubMedGoogle Scholar
  3. Ballard C, Gauthier S, Corbett A, Brayne C, Aarsland D, Jones E (2011) Alzheimer's disease. Lancet 377:1019–1031CrossRefPubMedGoogle Scholar
  4. Bolognesi ML, Minarini A, Rosini M, Tumiatti V, Melchiorre C (2008) From dual binding site acetylcholinesterase inhibitors to multi-target-directed ligands (MTDLs): a step forward in the treatment of Alzheimer's disease. Mini Rev Med Chem 8:960–967CrossRefPubMedGoogle Scholar
  5. Camps P, Cusack B, Mallender WD, el Achab RE, Morral J, Muñoz-Torrero D, Rosenberry TL (2000) Huprine X is a novel high-affinity inhibitor of acetylcholinesterase that is of interest for treatment of Alzheimer's disease. Mol Pharmacol 57:409–417PubMedGoogle Scholar
  6. Carlier PR, Chow ESH, Han Y, Liu J, Yazal JE, Pang YP (1999) Heterodimeric tacrine-based acetylcholinesterase inhibitors: investigating ligand-peripheral site interactions. J Med Chem 42:4225–4231CrossRefPubMedGoogle Scholar
  7. Chang L, Cui W, Yang Y, Xu S, Zhou W, Fu H, Hu S, Mak S, Hu J, Wang Q, Pui-Yan Ma V, Chung-lit Choi T, Dik-lung Ma E, Tao L, Pang Y, Rowan MJ, Anwyl R, Han Y, Wang Q (2015) Protection against beta-amyloid-induced synaptic and memory impairments via altering beta-amyloid assembly by bis(heptyl)-cognitin. Sci Rep 5:10256CrossRefPubMedPubMedCentralGoogle Scholar
  8. Greenblatt HM, Guillou C, Guénard D, Argaman A, Botti S, Badet B, Thal C, Silman I, Sussman JL (2004) The complex of a bivalent derivative of galanthamine with torpedo acetylcholinesterase displays drastic deformation of the active-site gorge: implications for structure-based drug design. J Am Chem Soc 126:15405–15411CrossRefPubMedGoogle Scholar
  9. Han RW, Zhang RS, Chang M, Peng YL, Wang P, Hu SQ, Choi CL, Yin M, Wang R, Han YF (2012) Reversal of scopolamine-induced spatial and recognition memory deficits in mice by novel multifunctional dimers bis-cognitins. Brain Res 1470:59–68CrossRefPubMedGoogle Scholar
  10. Haviv H, Wong DM, Greenblatt HM, Carlier PR, Pang YP, Silman I, Sussman JL (2005) Crystal packing mediates enantioselective ligand recognition at the peripheral site of acetylcholinesterase. J Am Chem Soc 127:11029–11036CrossRefPubMedGoogle Scholar
  11. Hu S, Cui W, Mak S, Tang J, Choi C, Pang Y, Han Y (2013a) Bis(propyl)-cognitin protects against glutamate-induced neuro-excitotoxicity via concurrent regulation of NO, MAPK/ERK and PI3-K/Akt/GSK3beta pathways. Neurochem Int 62:468–477CrossRefPubMedGoogle Scholar
  12. Hu YQ, Zhang J, Chandrashankra O, Ip FCF, Ip NY (2013b) Design, synthesis and evaluation of novel heterodimers of donepezil and huperzine fragments as acetylcholinesterase inhibitors. Bioorg Med Chem 21:676–683CrossRefPubMedGoogle Scholar
  13. Huang WY, Chao XJ, Ouyang Y, Liu AM, He XX, Chen MH, Wang LH, Liu J, Yu SW, Rapposelli S, Pi RB (2012) Tacrine-6-Ferulic acid, a novel multifunctional dimer against Alzheimer's disease, prevents oxidative stress-induced neuronal death through activating Nrf2/ARE/HO-1 pathway in HT22 cells. CNS Neurosci Ther 18:950–951CrossRefPubMedGoogle Scholar
  14. Ketcha Wanda GJ, Djiogue S, Zemo Gamo F, Guemnang Ngitedem S, Njamen D (2015) Anxiolytic and sedative activities of aqueous leaf extract of Dichrocephala integrifolia (Asteraceae) in mice. J Ethnopharmacol 176:494–498CrossRefPubMedGoogle Scholar
  15. Li W, Pi R, Chan HHN, Fu H, Lee NTK, Tsang HW, Pu Y, Chang DC, Li C, Luo J, Xiong K, Li Z, Xue H, Carlier PR, Pang Y, Tsim KWK, Li M, Han Y (2005) Novel dimeric acetylcholinesterase inhibitor bis7-tacrine, but not donepezil, prevents glutamate-induced neuronal apoptosis by blocking N-methyl-D-aspartate receptors. J Biol Chem 280:18179–18188CrossRefPubMedGoogle Scholar
  16. Li C, Carlier PR, Ren H, Kan KKW, Hui K, Wang H, Li W, Li Z, Xiong K, Clement EC, Xue H, Liu X, Li M, Pang Y, Han Y (2007) Alkylene tether-length dependent gamma-aminobutyric acid type a receptor competitive antagonism by tacrine dimers. Neuropharmacology 52:436–443CrossRefPubMedGoogle Scholar
  17. Liu T, Xia Z, Zhang WW, Xu JR, Ge XX, Li J, Cui Y, Qiu ZB, Xu J, Xie Q, Wang H, Chen HZ (2013) Bis(9)-(−)-nor-meptazinol as a novel dual-binding AChEI potently ameliorates scopolamine-induced cognitive deficits in mice. Pharmacol Biochem Behav 104:138–143CrossRefPubMedGoogle Scholar
  18. Lu Y, Wang C, Xue Z, Li C, Zhang J, Zhao X, Liu A, Wang Q, Zhou W (2015) PI3K/AKT/mTOR signaling-mediated neuropeptide VGF in the hippocampus of mice is involved in the rapid onset antidepressant-like effects of GLYX-13. Int J Neuropsychopharmacol 18Google Scholar
  19. Luo J, Li W, Zhao Y, Fu H, Ma DL, Tang J, Li C, Peoples RW, Li F, Wang Q, Huang P, Xia J, Pang Y, Han Y (2010) Pathologically activated neuroprotection via uncompetitive blockade of N-methyl-D-aspartate receptors with fast off-rate by novel multifunctional dimer bis(propyl)-cognitin. J Biol Chem 285:19947–19958CrossRefPubMedPubMedCentralGoogle Scholar
  20. Ma XC, Xin J, Wang HX, Zhang T, Tu ZH (2003) Acute effects of huperzine a and tacrine on rat liver. Acta Pharmacol Sin 24:247–250PubMedGoogle Scholar
  21. Mak S, Luk WWK, Cui W, Hu S, Tsim KWK, Han Y (2014) Synergistic inhibition on acetylcholinesterase by the combination of berberine and palmatine originally isolated from Chinese medicinal herbs. J Mol Neurosci 53:511–516CrossRefPubMedGoogle Scholar
  22. Rampa A, Belluti F, Gobbi S, Bisi A (2011) Hybrid-based multi-target ligands for the treatment of Alzheimer's disease. Curr Top Med Chem 11:2716–2730CrossRefPubMedGoogle Scholar
  23. Ratia M, Giménez-Llort L, Camps P, Muñoz-Torrero D, Clos MV, Badia A (2010) Behavioural effects and regulation of PKC alpha and MAPK by huprine X in middle aged mice. Pharmacol Biochem Behav 95:485–493CrossRefPubMedGoogle Scholar
  24. Rees T, Hammond PI, Soreq H, Younkin S, Brimijoin S (2003) Acetylcholinesterase promotes beta-amyloid plaques in cerebral cortex. Neurobiol Aging 24:777–787CrossRefPubMedGoogle Scholar
  25. Swale DR, Tong F, Temeyer KB, Li A, Lam PCH, Totrov MM, Carlier PR, Pérez de León AA, Bloomquist JR (2013) Inhibitor profile of bis(n)-tacrines and N-methylcarbamates on acetylcholinesterase from Rhipicephalus (Boophilus) microplus and Phlebotomus papatasi. Pestic Biochem Physiol 106:85–92CrossRefGoogle Scholar
  26. Terry AV, Buccafusco JJ (2003) The cholinergic hypothesis of age and Alzheimer's disease-related cognitive deficits: recent challenges and their implications for novel drug development. J Pharmacol Exp Ther 306:821–827CrossRefPubMedGoogle Scholar
  27. Van Dam D, De Deyn PP (2006) Model organisms - drug discovery in dementia: the role of rodent models. Nat Rev Drug Discov 5:956–970CrossRefPubMedGoogle Scholar
  28. Viola KL, Klein WL (2015) Amyloid beta oligomers in Alzheimer's disease pathogenesis, treatment, and diagnosis. Acta Neuropathol 129:183–206CrossRefPubMedPubMedCentralGoogle Scholar
  29. Wang WY, Yang Y, Ying C, Li W, Ruan H, Zhu X, You Y, Han Y, Chen R, Wang Y, Li M (2007) Inhibition of glycogen synthase kinase-3 beta protects doparninergic neurons from MPTP toxicity. Neuropharmacology 52:1678–1684CrossRefPubMedGoogle Scholar
  30. Wu Y, Luo X, Liu X, Liu D, Wang X, Guo Z, Zhu L, Tian Q, Yang X, Wang JZ (2015) Intraperitoneal Administration of a Novel TAT-BDNF peptide ameliorates cognitive impairments via modulating multiple pathways in two Alzheimer's rodent models. Sci Rep 5:15032CrossRefPubMedPubMedCentralGoogle Scholar
  31. Yan J, Sun L, Wu G, Yi P, Yang F, Zhou L, Zhang X, Li Z, Yang X, Luo H, Qiu M (2009) Rational design and synthesis of highly potent anti-acetylcholinesterase activity huperzine a derivatives. Bioorg Med Chem 17:6937–6941CrossRefPubMedGoogle Scholar
  32. Zhang HY, Tang XC (2006) Neuroprotective effects of huperzine a: new therapeutic targets for neurodegenerative disease. Trends Pharmacol Sci 27:619–625CrossRefPubMedGoogle Scholar
  33. Zhang HY, Yan H, Tang XC (2008) Non-cholinergic effects of huperzine a: beyond inhibition of acetylcholinesterase. Cell Mol Neurobiol 28:173–183CrossRefPubMedGoogle Scholar
  34. Zhang H, Mak S, Cui W, Li W, Han R, Hu S, Ye M, Pi R, Han Y (2011) Tacrine(2)-ferulic acid, a novel multifunctional dimer, attenuates 6-hydroxydopamine-induced apoptosis in PC12 cells by activating Akt pathway. Neurochem Int 59:981–988CrossRefPubMedGoogle Scholar
  35. Zhang J, Guo J, Zhao X, Chen Z, Wang G, Liu A, Wang Q, Zhou W, Xu Y, Wang C (2013) Phosphodiesterase-5 inhibitor sildenafil prevents neuroinflammation, lowers beta-amyloid levels and improves cognitive performance in APP/PS1 transgenic mice. Behav Brain Res 250:230–237CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2018

Authors and Affiliations

  • Huixin Chen
    • 1
  • Siying Xiang
    • 1
  • Ling Huang
    • 1
  • Jiajia Lin
    • 1
  • Shengquan Hu
    • 2
  • Shing-Hung Mak
    • 2
  • Chuang Wang
    • 1
  • Qinwen Wang
    • 1
  • Wei Cui
    • 1
  • Yifan Han
    • 2
  1. 1.Research Center of Behavioural Science, Department of Physiology, School of MedicineNingbo UniversityNingboChina
  2. 2.Department of Applied Biology and Chemistry Technology, Institute of Modern Chinese Medicinethe Hong Kong Polytechnic UniversityHung HomChina

Personalised recommendations