Login Register Cart 0
Generic placeholder image

Current Alzheimer Research

Editor-in-Chief

ISSN (Print): 1567-2050
ISSN (Online): 1875-5828

Back
Journal Home About Journal Editorial Board Journal Insight Current Issue Volumes/Issues
Subscribe Translate in Chinese
Research Article

Combination of Memantine and 6-Chlorotacrine as Novel Multi-Target Compound against Alzheimer’s Disease

Author(s): Martina Kaniakova, Eugenie Nepovimova, Lenka Kleteckova, Kristyna Skrenkova, Kristina Holubova, Zofia Chrienova, Vendula Hepnarova, Tomas Kucera, Tereza Kobrlova, Karel Vales, Jan Korabecny, Ondrej Soukup* and Martin Horak*

Volume 16, Issue 9, 2019

Page: [821 - 833] Pages: 13

DOI: 10.2174/1567205016666190228122218

Price: $65

Abstract

Background: Alzheimer’s disease (AD) is the most common form of dementia in the elderly. It is characterized as a multi-factorial disorder with a prevalent genetic component. Due to the unknown etiology, current treatment based on acetylcholinesterase (AChE) inhibitors and N–methyl-D-aspartate receptors (NMDAR) antagonist is effective only temporary. It seems that curative treatment will necessarily be complex due to the multifactorial nature of the disease. In this context, the so-called “multi-targeting" approach has been established.

Objectives: The aim of this study was to develop a multi-target-directed ligand (MTDL) combining the support for the cholinergic system by inhibition of AChE and at the same time ameliorating the burden caused by glutamate excitotoxicity mediated by the NMDAR receptors.

Methods: We have applied common approaches of organic chemistry to prepare a hybrid of 6-chlorotacrine and memantine. Then, we investigated its blocking ability towards AChE and NMDRS in vitro, as well as its neuroprotective efficacy in vivo in the model of NMDA-induced lessions. We also studied cytotoxic potential of the compound and predicted the ability to cross the blood-brain barrier.

Results: A novel molecule formed by combination of 6-chlorotacrine and memantine proved to be a promising multipotent hybrid capable of blocking the action of AChE as well as NMDARs. The presented hybrid surpassed the AChE inhibitory activity of the parent compound 6-Cl-THA twofold. According to results it has been revealed that our novel hybrid blocks NMDARs in the same manner as memantine, potently inhibits AChE and is predicted to cross the blood-brain barrier via passive diffusion. Finally, the MTDL design strategy was indicated by in vivo results which showed that the novel 6-Cl-THA-memantine hybrid displayed a quantitatively better neuroprotective effect than the parent compound memantine.

Conclusion: We conclude that the combination of two pharmacophores with a synergistic mechanism of action into a single molecule offers great potential for the treatment of CNS disorders associated with cognitive decline and/or excitotoxicity mediated by NMDARs.

Keywords: 6-Chlorotacrine, memantine, acetylcholinesterase, NMDA receptor, Alzheimer´s disease, ion channel, patch-clamp technique.

« Previous Next »
[1]
Saunders AM, Strittmatter WJ, Schmechel D, George-Hyslop PH, Pericak-Vance MA, Joo SH, et al. Association of apolipoprotein E allele epsilon 4 with late-onset familial and sporadic Alzheimer’s disease. Neurology 43(8): 1467-72. (1993).
[http://dx.doi.org/10.1212/WNL.43.8.1467] [PMID: 8350998]
[2]
Bartus RT, Dean RL III, Beer B, Lippa AS. The cholinergic hypothesis of geriatric memory dysfunction. Science 217(4558): 408-14. (1982).
[http://dx.doi.org/10.1126/science.7046051] [PMID: 7046051]
[3]
Hardy J, Selkoe DJ. The amyloid hypothesis of Alzheimer’s disease: Progress and problems on the road to therapeutics. Science 297(5580): 353-6. (2002).
[http://dx.doi.org/10.1126/science.1072994] [PMID: 12130773]
[4]
Maccioni RB, Muñoz JP, Barbeito L. The molecular bases of Alzheimer’s disease and other neurodegenerative disorders. Arch Med Res 32(5): 367-81. (2001).
[http://dx.doi.org/10.1016/S0188-4409(01)00316-2] [PMID: 11578751]
[5]
Swomley AM, Butterfield DA. Oxidative stress in Alzheimer disease and mild cognitive impairment: Evidence from human data provided by redox proteomics. Arch Toxicol 89(10): 1669-80. (2015).
[http://dx.doi.org/10.1007/s00204-015-1556-z] [PMID: 26126631]
[6]
Sanabria-Castro A, Alvarado-Echeverría I, Monge-Bonilla C. Molecular pathogenesis of alzheimer’s disease: an update. Ann Neurosci 24(1): 46-54. (2017).
[http://dx.doi.org/10.1159/000464422] [PMID: 28588356]
[7]
Butterfield DA, Pocernich CB. The glutamatergic system and Alzheimer’s disease: therapeutic implications. CNS Drugs 17(9): 641-52. (2003).
[http://dx.doi.org/10.2165/00023210-200317090-00004] [PMID: 12828500]
[8]
Greenamyre JT, Young AB. Excitatory amino acids and Alzheimer’s disease. Neurobiol Aging 10(5): 593-602. (1989).
[http://dx.doi.org/10.1016/0197-4580(89)90143-7] [PMID: 2554168]
[9]
Francis PT, Palmer AM, Snape M, Wilcock GK. The cholinergic hypothesis of Alzheimer’s disease: a review of progress. J Neurol Neurosurg Psychiatry 66(2): 137-47. (1999).
[http://dx.doi.org/10.1136/jnnp.66.2.137] [PMID: 10071091]
[10]
Adem A. Putative mechanisms of action of tacrine in Alzheimer’s disease. Acta Neurol Scand Suppl 139: 69-74. (1992).
[http://dx.doi.org/10.1111/j.1600-0404.1992.tb04458.x] [PMID: 1384265]
[11]
Horak M, Holubova K, Nepovimova E, Krusek J, Kaniakova M, Korabecny J, et al. The pharmacology of tacrine at N-methyl-d-aspartate receptors. Prog Neuropsychopharmacol Biol Psychiatry 75: 54-62. (2017).
[http://dx.doi.org/10.1016/j.pnpbp.2017.01.003] [PMID: 28089695]
[12]
Qizilbash N, Birks J, Lopez Arrieta J, Lewington S, Szeto S. WITHDRAWN: tacrine for Alzheimer’s disease. Cochrane Database Syst Rev (3): CD000202 (2007).
[PMID: 17636619]
[13]
Maresova P, Klimova B, Novotny M, Kuca K. Alzheimer’s and Parkinson’s diseases: expected economic impact on europe-a call for a uniform european strategy. J Alzheimers Dis 54(3): 1123-33. (2016).
[http://dx.doi.org/10.3233/JAD-160484] [PMID: 27567862]
[14]
Cavalli A, Bolognesi ML, Minarini A, Rosini M, Tumiatti V, Recanatini M, et al. Multi-target-directed ligands to combat neurodegenerative diseases. J Med Chem 51(3): 347-72. (2008).
[http://dx.doi.org/10.1021/jm7009364] [PMID: 18181565]
[15]
Prati F, Cavalli A, Bolognesi ML. Navigating the chemical space of multitarget-directed ligands: from hybrids to fragments in Alzheimer’s disease. Molecules 21(4): 466. (2016).
[http://dx.doi.org/10.3390/molecules21040466] [PMID: 27070562]
[16]
Zhang X, Rakesh KP, Bukhari SNA, Balakrishna M, Manukumar HM, Qin H-L. Multi-targetable chalcone analogs to treat deadly Alzheimer’s disease: current view and upcoming advice. Bioorg Chem 80: 86-93. (2018).
[http://dx.doi.org/10.1016/j.bioorg.2018.06.009] [PMID: 29890362]
[17]
Mezeiova E, Spilovska K, Nepovimova E, Gorecki L, Soukup O, Dolezal R, et al. Profiling donepezil template into multipotent hybrids with antioxidant properties. J Enzyme Inhib Med Chem 33(1): 583-606. (2018).
[http://dx.doi.org/10.1080/14756366.2018.1443326] [PMID: 29529892]
[18]
Simoni E, Daniele S, Bottegoni G, Trincavelli ML, Goldoni L, Tarozzo G, et al. Combining galantamine and memantine in multitargeted, new chemical entities potentially useful in Alzheimer’s disease. J Med Chem 2012; 55(22): 9708-21.
[http://dx.doi.org/10.1021/jm3009458] [PMID: 23033965]
[19]
Misik J, Nepovimova E, Pejchal J, Kassa J, Korabecny J, Soukup O. Cholinesterase inhibitor 6-chlorotacrine - in vivo toxicological profile and behavioural effects. Curr Alzheimer Res 15(6): 552-60. (2018).
[http://dx.doi.org/10.2174/1567205015666171212105412] [PMID: 29231138]
[20]
Sussman JL, Harel M, Frolow F, Oefner C, Goldman A, Toker L, et al. Atomic structure of acetylcholinesterase from Torpedo californica: a prototypic acetylcholine-binding protein. Science 253(5022): 872-9. (1991).
[http://dx.doi.org/10.1126/science.1678899] [PMID: 1678899]
[21]
Nepovimova E, Korabecny J, Dolezal R, Babkova K, Ondrejicek A, Jun D, et al. Tacrine-Trolox Hybrids: a novel class of centrally active, nonhepatotoxic multi-target-directed ligands exerting anticholinesterase and antioxidant activities with low in vivo toxicity. J Med Chem 58(22): 8985-9003. (2015).
[http://dx.doi.org/10.1021/acs.jmedchem.5b01325] [PMID: 26503905]
[22]
Roldán-Peña JM, Alejandre-Ramos D, López Ó, Maya I, Lagunes I, Padrón JM, et al. New tacrine dimers with antioxidant linkers as dual drugs: Anti-Alzheimer’s and antiproliferative agents. Eur J Med Chem 2017; 138: 761-73.
[http://dx.doi.org/10.1016/j.ejmech.2017.06.048] [PMID: 28728108]
[23]
Cheung J, Rudolph MJ, Burshteyn F, Cassidy MS, Gary EN, Love J, et al. Structures of human acetylcholinesterase in complex with pharmacologically important ligands. J Med Chem 55(22): 10282-6. (2012).
[http://dx.doi.org/10.1021/jm300871x] [PMID: 23035744]
[24]
Nachon F, Carletti E, Ronco C, Trovaslet M, Nicolet Y, Jean L, et al. Crystal structures of human cholinesterases in complex with huprine W and tacrine: elements of specificity for anti-Alzheimer’s drugs targeting acetyl- and butyryl-cholinesterase. Biochem J 453(3): 393-9. (2013).
[http://dx.doi.org/10.1042/BJ20130013] [PMID: 23679855]
[25]
Jeřábek J, Uliassi E, Guidotti L, Korábečný J, Soukup O, Sepsova V, et al. Tacrine-resveratrol fused hybrids as multi-target-directed ligands against Alzheimer’s disease. Eur J Med Chem 127: 250-62. (2017).
[http://dx.doi.org/10.1016/j.ejmech.2016.12.048] [PMID: 28064079]
[26]
Janockova J, Dolezal R, Nepovimova E, Kobrlova T, Benkova M, Kuca K, et al. Investigation of new orexin 2 receptor modulators using in silico and in vitro methods. Mol Basel Switz 23: 11. (2018).
[PMID: 30423961 ]
[27]
Malinak D, Dolezal R, Marek J, Salajkova S, Soukup O, Vejsova M, et al. 6-Hydroxyquinolinium salts differing in the length of alkyl side-chain: synthesis and antimicrobial activity. Bioorg Med Chem Lett 24(22): 5238-41. (2014).
[http://dx.doi.org/10.1016/j.bmcl.2014.09.060] [PMID: 25442318]
[28]
Kaniakova M, Krausova B, Vyklicky V, Korinek M, Lichnerova K, Vyklicky L, et al. Key amino acid residues within the third membrane domains of NR1 and NR2 subunits contribute to the regulation of the surface delivery of N-methyl-D-aspartate receptors. J Biol Chem 287(31): 26423-34. (2012).
[http://dx.doi.org/10.1074/jbc.M112.339085] [PMID: 22711533]
[29]
Lichnerova K, Kaniakova M, Park SP, Skrenkova K, Wang YX, Petralia RS, et al. Two N-glycosylation sites in the glun1 subunit are essential for releasing n-methyl-d-aspartate (NMDA) receptors from the endoplasmic reticulum. J Biol Chem 290(30): 18379-90. (2015).
[http://dx.doi.org/10.1074/jbc.M115.656546] [PMID: 26045554]
[30]
Kaniakova M, Kleteckova L, Lichnerova K, Holubova K, Skrenkova K, Korinek M, et al. 7-Methoxyderivative of tacrine is a ‘foot-in-the-door’ open-channel blocker of GluN1/GluN2 and GluN1/GluN3 NMDA receptors with neuroprotective activity in vivo. Neuropharmacology 140: 217-32. (2018).
[http://dx.doi.org/10.1016/j.neuropharm.2018.08.010] [PMID: 30099049]
[31]
Schmued LC, Albertson C, Slikker W Jr. Fluoro-Jade: a novel fluorochrome for the sensitive and reliable histochemical localization of neuronal degeneration. Brain Res 751(1): 37-46. (1997).
[http://dx.doi.org/10.1016/S0006-8993(96)01387-X] [PMID: 9098566]
[32]
Kleteckova L, Tsenov G, Kubova H, Stuchlik A, Vales K. Neuroprotective effect of the 3α5β-pregnanolone glutamate treatment in the model of focal cerebral ischemia in immature rats. Neurosci Lett 564: 11-5. (2014).
[http://dx.doi.org/10.1016/j.neulet.2014.01.057] [PMID: 24513236]
[33]
Korabecny J, Spilovska K, Mezeiova E, Benek O, Juza R, Kaping D, et al. A systematic review on donepezil-based derivatives as potential cholinesterase inhibitors for Alzheimer’s disease. Curr Med Chem (2018). 10.2174/0929867325666180517094023.
[http://dx.doi.org/10.2174/0929867325666180517094023] [PMID: 29768996]
[34]
Arendt T, Brückner MK, Lange M, Bigl V. Changes in acetylcholinesterase and butyrylcholinesterase in Alzheimer’s disease resemble embryonic development--a study of molecular forms. Neurochem Int 21(3): 381-96. (1992).
[http://dx.doi.org/10.1016/0197-0186(92)90189-X] [PMID: 1303164]
[35]
Cheewakriengkrai L, Gauthier S. A 10-year perspective on donepezil. Expert Opin Pharmacother 14(3): 331-8. (2013).
[http://dx.doi.org/10.1517/14656566.2013.760543] [PMID: 23316713]
[36]
Hershkowitz N, Rogawski MA. Tetrahydroaminoacridine block of N-methyl-D-aspartate-activated cation channels in cultured hippocampal neurons. Mol Pharmacol 39(5): 592-8. (1991).
[PMID: 1709720]
[37]
Vorobjev VS, Sharonova IN. Tetrahydroaminoacridine blocks and prolongs NMDA receptor-mediated responses in a voltage-dependent manner. Eur J Pharmacol 253(1-2): 1-8. (1994).
[http://dx.doi.org/10.1016/0014-2999(94)90750-1] [PMID: 8013535]
[38]
Costa AC, Albuquerque EX. Dynamics of the actions of tetrahydro-9-aminoacridine and 9-aminoacridine on glutamatergic currents: concentration-jump studies in cultured rat hippocampal neurons. J Pharmacol Exp Ther 268(1): 503-14. (1994).
[PMID: 7507997]
[39]
Sobolevskii AI, Khodorov BI. Blocker studies of the functional architecture of the NMDA receptor channel. Neurosci Behav Physiol 32(2): 157-71. (2002).
[http://dx.doi.org/10.1023/A:1013927409034] [PMID: 11942695]
[40]
Vyklicky V, Krausova B, Cerny J, Balik A, Zapotocky M, Novotny M, et al. Block of NMDA receptor channels by endogenous neurosteroids: implications for the agonist induced conformational states of the channel vestibule. Sci Rep 5: 10935. (2015).
[http://dx.doi.org/10.1038/srep10935] [PMID: 26086919]
[41]
Blanpied TA, Boeckman FA, Aizenman E, Johnson JW. Trapping channel block of NMDA-activated responses by amantadine and memantine. J Neurophysiol 77(1): 309-23. (1997).
[http://dx.doi.org/10.1152/jn.1997.77.1.309] [PMID: 9120573]
[42]
Kotermanski SE, Wood JT, Johnson JW. Memantine binding to a superficial site on NMDA receptors contributes to partial trapping. J Physiol 587(Pt 19): 4589-604. (2009).
[http://dx.doi.org/10.1113/jphysiol.2009.176297] [PMID: 19687120]
[43]
Rambousek L, Kleteckova L, Kubesova A, Jirak D, Vales K, Fritschy J-M. Rat intra-hippocampal NMDA infusion induces cell-specific damage and changes in expression of NMDA and GABAA receptor subunits. Neuropharmacology 105: 594-606. (2016).
[http://dx.doi.org/10.1016/j.neuropharm.2016.02.035] [PMID: 26930443]
[44]
Orgogozo J-M, Rigaud A-S, Stöffler A, Möbius H-J, Forette F. Efficacy and safety of memantine in patients with mild to moderate vascular dementia: a randomized, placebo-controlled trial (MMM 300). Stroke 33(7): 1834-9. (2002).
[http://dx.doi.org/10.1161/01.STR.0000020094.08790.49] [PMID: 12105362]
[45]
Reisberg B, Doody R, Stöffler A, Schmitt F, Ferris S, Möbius HJ. Memantine in moderate-to-severe Alzheimer’s disease. N Engl J Med 348(14): 1333-41. (2003).
[http://dx.doi.org/10.1056/NEJMoa013128] [PMID: 12672860]

Rights & Permissions Print Cite
Article Metrics
38
3
© 2024 Bentham Science Publishers | Privacy Policy