Tacrine and its derivatives in the therapy of Alzheimer’s disease

1. Alzheimer’s Association: 2012 Alzheimer’s disease facts and figures. Alzheimers Dement. 2012; 8, 131–168.

2. Chopra K., Misra S., Kuhad A. Current perspectives on pharmacotherapy of Alzheimer’s disease. Expert Opin. Pharmacother. 2011; 12, 335–350.

3. Launer L. J., Fratiglioni L., Andersen K., Breteler M. M. B., Copeland R. J. M., Dartiques J. F., Lobo A., Martinez-Lage J., Soininen H., Hofman A. Regional differences in the incidence of dementia in Europe: EURODEM collaborative analyses 1999. Collective authors of Alzheimer Europe organization: Dementia in Europe Yearbook: 2008, 20; 1–178.

4. Weiner M. W., Aisen P. S., Clifford R. J. Jr., Jagust W. J., Trojanowski J. Q., Shaw L., Saykin A. J., Morris J. C., Cairns N., Beckett L. A., Toga A., Green R., Walter S., Soares H., Snyder P., Siemers E., Potter W., Cole P. E., Schmidt M. The Alzheimer’s disease neuroimaging initiative: Progress report and future plans. Alzheimers Dement. 2010; 6, 202–211.

5. Green R. C., Cupples L. A., Go R., Benke K. S., Edeki T., Griffith P. A., Williams M., Hipps Y., Graff-Radford N., Bachman D., Farrer L. A. MIRAGE Study Group. Risk of dementia among white and African-American relatives of patients with Alzheimer’s disease. J. Am. Med. Assoc. 2002; 287, 329–336.

6. Drtinová L., Pohanka M. Alzheimerova demence: aspekty současné farmakologické léčby. Čes. slov. Farm. 2011; 60, 219–228.

7. Bartus R. T., Dean R. L., Beer B., Lippa A. S. The cholinergic hypothesis of geriatric memory dysfunction. Science 1982; 217, 408–414.

8. Bartus R. T., Dean R. L., Goas J. A., Lippa A. S. Age-related changes in passive avoidance retention: modulation with dietary choline. Science 1980; 209, 301–303.

9. Perry E. K., Tomlinson B. E., Blessed G., Perry R. H., Cross A. J., Crow T. T. Noradrenergic and cholinergic systems in senile dementia of Alzheimer type. Lancet 1981; 2, 8238–8249.

10. Drachman D. A. Memory and cognitive function in man: does the cholinergic system have a specific role? Neurology 1977; 27, 783–790.

11. Bowen D. M., Smith C. B., White P., Davison A. N. Neurotransmitter-related enzymes and indices of hypoxia in senile dementia and other abiotrophies. Brain 1976; 99, 459–496.

12. Davies P., Maloney A. J. F. Selective loss of central cholinergic neurones in Alzheimer’s disease. Lancet 1976; 2, 1403.

13. Perry E. K., Gibson P. H., Blessed G., Perry R. H., Tomlinson B. E. Neurotransmitter enzyme abnormalities in senile dementia. Choline acetyltransferase and glutamic acid decarboxylase activities in necropsy brain tissue. J. Neurol. Sci. 1977; 34, 247–265.

14. Drachman D. A., Leavitt J. Human memory and the cholinergic system. Arch. Neurol. 1974; 30, 113–121.

15. Bartus R. T., Dean R. L., Beer B., Lippa A. S. The cholinergic hypothesis of geriatric memory dysfunction. Science 1982; 217, 408–417.

16. Albert A. The chemical and biological properties of acridines. Sci. Prog. 1949; 37, 418–434.

17. Valenti P., Rampa A., Bisi A., Andrisano V., Cavrini V., Fin L., Buriani A., Giusti P. Acetylcholinesterase inhibition by tacrine analogues. Bioorg. Med. Chem. Lett. 1997; 7, 2599–2602.

18. Lee N. Y., Choi H. O., Kang Y. S. The acetylcholinesterase inhibitors competitively inhibited an acetyl L-carnitine transport through the blood-brain barrier. Neurochem. Res. 2012; 37, 1499–1507.

19. Inestrosa N. C., Alvarez A., Pérez C. A., Moreno R. D., Vicente M., Linker C., Casanueva O. I., Soto C., Garrido J. Acetylcholinesterase accelerates assembly of amyloid-beta-peptides into Alzheimer’s fibrils: possible role of the peripheral site of the enzyme. Neuron. 1996; 16, 881–891.

20. Recanatini M., Cavalli A., Belluti F., Piazzi L., Rampa A., Bisi A., Gobbi S., Valenti P., Andrisano V., Bartolini M., Cavrini V. SAR of 9-amino-1,2,3,4-tetrahydroacridine-based acetylcholinesterase inhibitors: Synthesis, enzyme inhibitory activity, QSAR, and structure-based CoMFA of tacrine analogues. J. Med. Chem. 2000; 43, 2007–2018.

21. dos Santos Pisoni D., Sobieski da Costa J., Gamba D., Petzhold C. L., de Amorim Borges A. C., Ceschi M. A., Lunardi P., Saraiva Gonçalves C. A. Synthesis and AChE inhibitory activity of new chiral tetrahydroacridine analoques from terpenic cyclanones. Eur. J. Med. Chem. 2010; 45, 526–535.

22. Hamuľakova S., Kristian P., Jun D., Kuca K., Imrich J., Danihel I., Bőhm S., Klika K. D. Synthesis, structure, and cholinergic effect of novel neuroprotective compounds bearing the tacrine pharmacophore. Heterocycles 2008; 76, 1219–1235.

23. Marco-Contelles J., León R., de Los Ríos C., Guglietta A., Terencio J., López M. G., García A. G., Villarroya M. Novel multipotent tacrine-dihydropyridine hybrids with improved acetylcholinesterase inhibitory and neuroprotective activities as potential drugs for the treatment of Alzheimer’s disease. J. Med. Chem. 2006; 49, 7607–7610.

24. Marco-Contelles J., León R., de los Ríos C., Samadi A., Bartolini M., Andrisano V., Huertas O., Barril X., Luque F. J., Rodríguez-Franco M. I., López B., López M. G., García A. G., Carreiras Mdo. C., Villarroya M. Tacripyrines, the first tacrine-dihydropyridine hybrids, as multitarget-directed ligands for the treatment of Alzheimer’s disease. J. Med. Chem. 2009; 52, 2724–2732.

25. Samadi A., Valderas C., de los Ríos C., Bastida A., Chioua M., González-Lafuente L., Colmena I., Gandía L., Romero A., Del Barrio L., Martín-de-Saavedra M. D., López M. G., Villarroya M., Marco-Contelles J. Cholinergic and neuroprotective drugs for the treatment of Alzheimer and neuronal vascular diseases. II. Synthesis, biological assessment, and molecular modelling of new tacrine analogues from highly substituted 2-aminopyridine-3-carbonitriles. Bioorg. Med. Chem. 2011; 19, 122–133.

26. Dejmek L. 7-MEOTA. Drugs Future 1990, 15, 126–129.

27. Patocka J., Jun D., Kuca K. Possible role of hydroxylated metabolites of tacrine in drug toxicity and therapy of Alzheimer’s disease. Curr. Drug Metab. 2008; 9, 332–335.

28. Korabecny J., Musilek K., Holas O., Binder J., Zemek F., Marek J., Pohanka M., Opletalova V., Dohnal V., Kuca K. Synthesis and in vitro evaluation of N-alkyl-7-methoxytacrine hydrochlorides as potential cholinestrase inhibitors in Alzhemeir disease. Bioorg. Med. Chem. Lett. 2010; 20, 6093–6095.

29. Korabecny J., Musilek K., Holas O., Nepovimova E., Jun D., Zemek F., Opletalova V., Patocka J., Dohnal V., Nachon F., Hroudova J., Fisar Z., Kuca K. Synthesis and in vitro evaluation of N-(bromobut-3-en-2-yl)-7-methoxy-1,2,3,4-tetrahydroacridin-9-amine as a cholinesterase inhibitor with regard to Alzheimer‘s disease treatment. Molecules 2010; 15, 8804–8812.

30. Korabecny J., Musilek K., Zemek F., Horova A., Holas O., Nepovimova E., Opletalova V., Hroudova J., Fisar Z., Jung Y.-S., Kuca K. Synthesis and in vitro evaluation of 7-methoxy-N-(pent-4-enyl)-1,2,3,4-tetrahydroacridin-9-amine – new tacrine derivative with cholinergic properties. Bioorg. Med. Chem. Lett. 2011; 21, 6563–6566.

31. Hroudova J., Fisar Z., Korabecny J., Kuca K. In vitro effects of acetylcholinesterase inhibitors and reactivators on Complex I of electron transport chain. Neuroendocrinol. Lett. 2011; 32, 259–263.

32. Defaux J., Sala M., Formosa X., Galdeano C., Taylor M. C., Alobaid W. A., Kelly J. M., Wright C. W., Camps P., Muñoz- -Torrero D. Huprines as a new family of dual acting trypanocidal-antiplasmodial agents. Bioorg. Med. Chem. 2011; 19, 1702–1707.

33. Vanlaer S., Voet A., Gielens C., De Maeyer M., Compernolle F. Bridged 5,6,7,8-tetrahydro-1,6-naphthyridines, analogues of huperzine A: Synthesis, modelling studies and evaluation as inhibitors of acetylcholinesterase. Eur. J. Org. Chem. 2009; 643–654.

34. Camps P., Contreras J., Font-Bardia M., Morral J., Muñoz- -Torrero D., Solans X. Enantioselective synthesis of tacrine-huperzine A hybrids. Preparative chiral MPLC separation of their racemic mixtures and absolute configuration assignments by X-ray diffraction analysis. Tetrahedron-Asymmetr. 1998; 9, 835–849.

35. Ronco C., Jean L., Renard P.-Y. Improved synthetic pathway for the derivatization of huprine scaffold. Tetrahedron 2010; 66, 7399–7404.

36. Camps P., El Achab R., Morral J., Muñoz-Torrero D., Badia A., Baños J. E., Vivas N. M., Barril X., Orozco M., Luque F. J. New tacrine-huperzine A hybrids (huprines): Highly potent tight-binding acetylcholinesterase inhibitors of interest for the treatment of Alzheimer’s disease J. Med. Chem. 2000; 43, 4657–4666.

37. Pang Y. P., Quiram P., Jelacic T., Hong F., Brimijoin S. Highly potent, selective, and low cost bis-tetrahydroaminacrine inhibitors of acetylcholinesterase. Steps toward novel drugs for treating Alzheimer’s disease. J. Biol. Chem. 1996; 271, 23646–23649.

38. Rydberg E. H., Brumshtein B., Greenblatt H. M., Wong D. M., Shaya D., Williams L. D., Carlier P. R., Pang Y. P., Silman I., Sussman J. L. Complexes of alkylene-linked tacrine dimers with Torpedo californica acetylcholinesterase: Binding of bis5-tacrine produces a dramatic rearrangement in the active-site gorge. J. Med. Chem. 2006; 49, 5491–5500.

39. Yu H., Li W. M., Kan K. K., Ho J. M., Carlier P. R., Pang Y. P., Gu Z. M., Zhong Z., Chan K., Wang Y. T., Han Y. F. The physicochemical properties and the in vivo AChE inhibition of two potential anti-Alzheimer agents, bis(12)-hupyridone and bis(7)-tacrine. J. Pharm. Biomed. Anal. 2008; 46, 75–81.

40. Li W., Xue J., Niu C., Fu H., Lam C. S., Luo J., Chan H. H., Xue H., Kan K. K., Lee N. T., Li C., Pang Y., Li M., Tsim K. W., Jiang H., Chen K., Li X., Han Y. Synergistic neuroprotection by bis(7)-tacrine via concurrent blockade of N-methyl-D--aspartate receptors and neuronal nitric-oxide synthase. Mol. Pharmacol. 2007; 71, 1258–1267.

41. Li C., Carlier P. R., Ren H., Kan K. K., Hui K., Wang H., Li W., Li Z., Xiong K., Clement E. C., Xue H., Liu X., Li M., Pang Y., Han Y. Alkylene tether-length dependent gamma aminobutyric acid type A receptor competitive antagonism by tacrine dimers. Neuropharmacology 2007; 52, 436–443.

42. Zhou L., Liu Y. W., Peoples R. W., Yang M., Tian X., Ai Y. X., Pang Y. P., Li Z. W., Han Y. F., Li C. Y. Mechanism of bis(7)-tacrine inhibition of GABA: activated current in cultured rat hippocampal neurons. Neuropharmacology 2009; 57, 33–40.

43. Korabecny J., Holas O., Musilek K., Pohanka M., Opletalova V., Dohnal V., Kuca K. Synthesis and in vitro evaluation of new tacrine derivatives-bis-alkylene linked 7-MEOTA. Lett. Org. Chem. 2010; 7, 327–331.

44. Wlodek S. T., Antosiewicz J., McCammon J. A., Straatsma T. P., Gilson M. K., Briggs J. M., Humblet C., Sussman J. L. Binding of tacrine and 6‑chlorotacrine by acetylcholinesterase. Biopolymers 1996; 38, 109–117.

45. Rosini M., Simoni E., Bartolini M., Cavalli A., Ceccarini L., Pascu N., McClymont D. W., Tarozzi A., Bolognesi M. L., Minarini A., Tumiatti V., Andrisano V., Mellor I. R., Melchiorre C. Inhibition of acetylcholinesterase, beta-amyloid aggregation, and NMDA receptors in Alzheimer’s disease: a promising direction for the multi-target-directed ligands gold rush. J. Med. Chem. 2008; 51, 4381–4384.

46. Alonso D., Dorronsoro I., Rubio L., Muñoz P., Garcia-Palomero E., Del Monte M., Bidon-Chanal A., Orozco M., Luque F. J., Castro A., Medina M., Martinez A. Donepezil-tacrine hybrid related derivatives as new dual binding site inhibitors of AChE. Bioorg. Med. Chem. 2005; 13, 6588–6597.

47. Muñoz-Torrero D., Camps P. Dimeric and hybrid anti-Alzheimer drug candidates. Curr. Med. Chem. 2006; 13, 399–422.

48. Carlier P. R., Du D. M., Han Y., Liu J., Pang Y. P. Potent, easily synthesized huperzine A-tacrine hybrid acetylcholinesterase inhibitors. Bioorg. Med. Chem. Lett. 1999; 9, 2335–2338.

49. Musial A., Bajda M., Malawska B. Recent developments in cholinesterases inhibitors for Alzheimer’s disease treatment. Curr. Med. Chem. 2007; 14, 2654–2679.

50. Decker M. Recent advances in the development of hybrid molecules/designed multiple compounds with antiamnesic properties. Mini Rev. Med. Chem. 2007; 7, 221–229.

51. Li W. M., Kan K. K., Carlier P. R., Pang Y. P., Han Y. F. East meets West in the search for Alzheimer’s therapeutics - novel dimeric inhibitors from tacrine and huperzine A. Curr. Alzheimer Res. 2007; 4, 386–396.

52. Jiang H., Luo X., Bai D. Progress in clinical, pharmacological, chemical and structural biological studies of huperzine A: a drug of traditional Chinese medicine origin for the treatment of Alzheimer’s disease. Curr. Med. Chem. 2003; 10, 2231–2252.

53. Fang L., Kraus B., Lehmann J., Heilmann J., Zhang Y., Decker M. Design and synthesis of tacrine-ferulic acid hybrids as multipotent anti-Alzheimer drug candidates. Bioorg. Med. Chem. Lett. 2008; 18, 2905–2909.

54. Heilmann J., Calis I., Kirmizibekmez H., Schuhly W., Harput S., Sticher O. Radical scavenger activity of phenylethanoid glycosides in FMLP stimulated human polymorphonuclear leukocytes: structure-activity relationships. Planta Med. 2000; 66, 746–748.

55. Yan J. J., Cho J. Y., Kim H. S., Kim K. L., Jung J. S., Huh S. O., Suh H. W., Kim Y. H., Song D. K. Protection against beta-amyloid peptide toxicity in vivo with long-term administration of ferulic acid. Br. J. Pharmacol. 2001; 133, 89–96.

56. Davalos A., Gomez-Cordoves C., Bartolome B. Extending applicability of the oxygen radical absorbance capacity (ORAC fluorescein) assay. J. Agric. Food Chem. 2004; 52, 48–54.

57. Pi R., Mao X., Chao X., Cheng Z., Liu M., Duan X., Ye M., Chen X., Mei Z., Liu P., Li W., Han Y. Tacrine-6-ferulic acid, a novel multifunctional dimer, inhibits amyloid-ββ-mediated Alzheimer’s disease-associated pathogenesis in vitro and in vivo. PLoS One. 2012; 7, Epub.

58. Fernández-Bachiller M. I., Pérez C., Campillo N. E., Páez J. A., González-Muñoz G. C., Usán P., García-Palomero E., López M. G., Villarroya M., García A. G., Martínez A., Rodríguez-Franco M. I. Tacrine-melatonin hybrids as multifunctional agents for Alzheimer’s disease, with cholinergic, antioxidant, and neuroprotective properties. ChemMedChem. 2009; 4, 828–841.

59. Nunomura R. J., Castellani X., Zhu P. I., Moreira G., Perry M. A., Smith J. Involvement of oxidative stress in Alzheimer disease. Neuropathol. Exp. Neurol. 2006; 65, 631–641.

60. Reiter R. J., Tan D.-X., Manchester L. C., Terron M. P., Flores L. J., Koppisepi S. Medical implications of melatonin: receptor-mediated and receptor-independent actions. Adv. Med. Sci. 2007; 52, 11–28.

61. Masilamoni J. G., Jesudason E. P., Dhandayuthapani S., Ashok B. S., Vignesh S., Jebaraj W. C., Paul S. F., Jayakumar R. The neuroprotective role of melatonin against amyloid beta peptide injected mice. Free Radical. Res. 2008; 42, 661–673.

62. Rodríguez-Franco M. I., Fernández-Bachiller M. I., Pérez C., Hernández-Ledesma B., Bartolomé B. Novel tacrine-melatonin hybrids as dual-acting drugs for Alzheimer disease, with improved acetylcholinesterase inhibitory and antioxidant properties. J. Med. Chem. 2006; 49, 459–462.

63. Lysko P. G., Lysko K. A., Webb C. L., Feuerstein G., Mason P. E., Walter M. F., Mason R. P. Neuroprotective activities of carvedilol and a hydroxylated derivative: role of membrane biophysical interactions. Biochem. Pharmacol. 1998; 56, 1645–1656.

64. Rosini M., Simoni E., Bartolini M., Cavalli A., Ceccarini L., Pascu N., McClymont D. W., Tarozzi A., Bolognesi M. L., Minarini A., Tumiatti V., Andrisano V., Mellor I. R., Melchiorre C. Inhibition of acetylcholinesterase, beta-amyloid aggregation, and NMDA receptors in Alzheimer’s disease: a promising direction for the multi-target-directed ligands gold rush. J. Med. Chem. 2008; 51, 4381–4384.

65. Malinski T. Nitric oxide and nitroxidative stress in Alzheimer’s disease. J. Alzheimers Dis. 2007; 11, 207–218.

66. Fang L., Appenroth D., Decker M., Kiehntopf M., Lupp A., Peng S., Fleck C., Zhang Y., Lehmann J. NO-donating tacrine hybrid compounds improve scopolamine-induced cognition impairment and show less hepatotoxicity. J. Med. Chem. 2008; 51, 7666–7669.

67. Elsinghorst P. W., Cieslik J. S., Mohr K., Tränkle C., Gütschow M. First gallamine-tacrine hybrid: design and characterization at cholinesterases and the M2 muscarinic receptor. J. Med. Chem. 2007; 50, 5685–5695.

68. Camps P., Formosa X., Galdeano C., Gómez T., Muñoz-Torrero D., Scarpellini M., Viayna E., Badia A., Clos M. V., Camins A., Pallàs M., Bartolini M., Mancini F., Andrisano V., Estelrich J., Lizondo M., Bidon-Chanal A., Luque F. J. Novel donepezil-based inhibitors of acetyl- and butyrylcholinesterase and acetylcholinesterase-induced beta-amyloid aggregation. J. Med. Chem. 2008; 51, 3588–3598.

69. Camps P., Formosa X., Galdeano C., Muñoz-Torrero D., Ramírez L., Gómez E., Isambert N., Lavilla R., Badia A., Clos M. V., Bartolini M., Mancini F., Andrisano V., Arce M. P., Rodríguez-Franco M. I., Huertas O., Dafni T., Luque F. J. Pyrano[3,2-c]quinoline-6-chlorotacrine hybrids as a novel family of acetylcholinesterase- and beta-amyloid-directed anti-Alzheimer compounds. J. Med. Chem. 2009; 52, 5365–5379.

70. Morris M. C., Schneider J. A., Tangney C. C. Thoughts on B-vitamins and dementia. J. Alzheimers Dis. 2006; 9, 429–433.

71. Morris M. C., Evans D. A., Bienias J. L., Scherr P. A., Tangney C. C., Hebert L. E., Bennett D. A., Wilson R. S., Aggarwal N. Dietary niacin and the risk of incident Alzheimer’s disease and of cognitive decline. J. Neurol. Neurosurg. Psychiatry. 2004; 75, 1093–1099.

72. Szymański P., Markowicz M., Mikiciuk-Olasik E. Synthesis and biological activity of derivatives of tetrahydroacridine as acetylcholinesterase inhibitors. Bioorg. Chem. 2011; 39, 138–142.

73. Galdeano C., Viayna E., Sola I., Formosa X., Camps P., Badia A., Clos M. V., Relat J., Ratia M., Bartolini M., Mancini F., Andrisano V., Salmona M., Minguillón C., González-Muñoz G. C., Rodríguez-Franco M. I., Bidon-Chanal A., Luque F. J., Muñoz-Torrero D. Huprine-tacrine heterodimers as anti-amyloidogenic compounds of potential interest against Alzheimer’s and prion diseases. J. Med. Chem. 2012; 55, 661–669.

74. Hamulakova S., Janovec L., Hrabinova M., Kristian P., Kuca K., Banasova M., Imrich J. Synthesis, design and biological evaluation of novel highly potent tacrine congeners for the treatment of Alzheimer’s disease. Eur. J. Med. Chem. 2012; 55, 23–31.