Multifunctional enzyme inhibition for neuroprotection - A focus on MAO, NOS, and AChE inhibitors

Drug Design and Discovery in Alzheimer's Disease

Volumn , Issue , 2014, Pages 291-365

  Joubert, Jacques ^a   Petzer, Jacobus P ^b   Prins, Louis H A ^c   Repsold, Benjamin P ^b   Malan, Sarel F ^a  

^a UNIVERSITY OF THE WESTERN CAPE   (South Africa)

^b NORTH WEST UNIVERSITY   (South Africa)

^c UNIVERSITY OF NAMIBIA   (Namibia)

Author keywords

Acetylcholinesterase; Alzheimer's and parkinson's disease; Drug design; Monoamine oxidase; Multi target directed ligands; Neurodegenerative disorders; Nitric oxide synthase

Indexed keywords

DRUG INTERACTIONS; ENZYME INHIBITION; NITRIC OXIDE;

ACETYLCHOLINESTERASE; DRUG DESIGN; MONOAMINE OXIDASE; MULTI-TARGETS; NEURODEGENERATIVE DISORDERS; NITRIC-OXIDE SYNTHASE; PARKINSON'S DISEASE;

NEURODEGENERATIVE DISEASES;

EID: 84940885311     PISSN: None     EISSN: None     Source Type: Book    
DOI: 10.1016/B978-0-12-803959-5.50005-2     Document Type: Chapter

References (278)

1. McLean, C.A.; Cherny, R.A.; Fraser, F.W.; Fuller, S.J.; Smith, M.J.; Beyreuther, K.; Bush, A.I.; Masters, C.L. Soluble pool of Abeta amyloid as a determinant of severity of neurodegeneration in Alzheimer's disease. Ann. Neurol., 1999, 46, 860-866.
2. Naslund, J.; Haroutunian, V.; Mohs, R.; Davis, K.L.; Davies, P.; Greengard, P.; Buxbaum, J.D. Correlation between elevated levels of amyloid beta-peptide in the brain and cognitive decline. JAMA, 2000, 283, 1571-1577.
3. Dauer, W.; Przedborski, S. Parkinson's disease: mechanisms and models. Neuron, 2003, 39(6), 889-909.
4. Jellinger, K.A. General aspects of neurodegeneration. J. Neural. Transm., 2003, 65, 101.
5. Smid, P.; Coolen, H.K.A.C.; Keizer, H. G.; Van Hes, R.; De Moes, J.P.; Den Hartog, A.P.; Stork, B.; Plekkenpol, R.H.; Niemann, L.C.; Stroomer, C.N.J.; Tulp, M.T.M.; Van Stuivenberg, H.H.; McCreary, A.C.; Hesselink, M.B.; Herremans, A.H.J.; Kruse, C.G. Synthesis, structure-activity relationships, and biological properties of 1-heteroaryl-4-[omega-(1H-indol-3-yl)alkyl]piperazines, novel potential antipsychotics combining potent dopamine D2 receptor antagonism with potent serotonin reuptake inhibition. J. Med. Chem., 2005, 48, 6855.
6. Van der Schyf, C.J.; Geldenhuys, W.J.; Youdim, M.B. Multifunctional drugs with different CNS targets for neuropsychiatric disorders. J. Neurochem., 2006, 99, 1033-1048.
7. Morphy, R.; Rankovic, Z. Designed multiple ligands. An emerging drug discovery paradigm. J. Med. Chem., 2005, 48, 6523-6543.
8. Cavalli, A.; Bolognesi, M.L.; Minarini, A.; Rosini, M.; Tumiatti, V.; Recanatini, M.; Melchiorre, C. Multi-target-directed ligands to combat neurodegenerative diseases. J. Med. Chem., 2008, 51, 347-372.
9. Youdim, M.B.; Buccafusco, J.J. Multi-functional drugs for various CNS targets in the treatment of neurodegenerative disorders. Trends Pharmacol. Sci., 2005, 26, 27-35.
10. Marlatt, M.W.; Webber, K.M.; Moreira, P.I.; Lee, H.G.; Casadesus, G.; Honda, K.; Zhu, X.; Perry, G.; Smith, M. A. Therapeutic opportunities in Alzheimer disease: one for all or all for one? Curr. Med. Chem., 2005, 12, 1137-1147.
11. Youdim, M.B.; Edmondson, D.; Tipton, K.F. The therapeutic potential of monoamine oxidase inhibitors. Nat. Rev. Neurosci., 2006, 7, 295-309.
12. Youdim, M.B.; Weinstock, M. Therapeutic applications of selective and non-selective inhibitors of monoamine oxidase A and B that do not cause significant tyramine potentiation. Neurotoxicology, 2004, 25, 243-250.
13. Riederer, P.; Lachenmayer, L.; Laux, G. Clinical applications of MAO-inhibitors. Curr. Med. Chem., 2004, 11, 2033-2043.
14. Moncada, S.; Palmer, R.M.; Higgs, E.A. Nitric oxide: physiology, pathophysiology, and pharmacology. Pharmacol. Rev., 1991, 43, 109-142.
15. Southan G.J.; Szabó, C. Selective pharmacological inhibition of distinct nitric oxide synthase isoforms. Biochem. Pharmacol., 1996, 51, 383-394.
16. Mori, E.; Hashimoto, M.; Krishnan, K. R.; Doraiswamy, P. M. What constitutes clinical evidence for neuroprotection in Alzheimer disease: support for the cholinesterase inhibitors? Alzheimer. Dis. Assoc. Disord., 2006, 20, S19-26.
17. Youdim, M.B.; Bakhle, Y.S. Monoamine oxidase: isoforms and inhibitors in Parkinson's disease and depressive illness. Br. J. Pharmacol., 2006, 147, S287-S296.
18. Edmondson, D.E.; Binda, C.; Mattevi, A. The FAD binding sites of human monoamine oxidases A and B. Neurotoxicology, 2004, 25, 63-72.
19. Shih, J.C.; Chen. K.; Ridd. M.J. Monoamine oxidase: from genes to behavior. Annu. Rev. Neurosci., 1999, 22, 197-217.
20. Son, S.Y.; Ma, J.; Kondou, Y.; Yoshimura, M.; Yamashita, E.; Tsukihara, T. Structure of human monoamine oxidase A at 2.2-A resolution: the control of opening the entry for substrates/inhibitors. Proc. Natl. Acad. Sci. USA, 2008, 105(15), 5739-5744.
21. Binda, C.; Newton-Vinson, P.; Hubálek, F.; Edmondson, D.E., Mattevi, A. Structure of human monoamine oxidase B, a drug target for the treatment of neurological disorders. Nat. Struct. Biol., 2002, 9(1), 22-26.
22. Edmondson, D.E.; Binda, C.; Wang, J.; Upadhyay, A.K.; Mattevi, A. Molecular and mechanistic properties of the membrane-bound mitochondrial monoamine oxidases. Biochemistry, 2009, 48(20), 4220-4230.
23. Walker, W.H.; Kearney, E.B.; Seng, R.L.; Singer, T.P. The covalently-bound flavin of hepatic monoamine oxidase. 2. Identification and properties of cysteinyl riboflavin. Eur. J. Biochem., 1971, 24(2), 328-331.
24. Kearney, E.B.; Salach, J.I.; Walker, W.H.; Seng, R.L.; Kenney, W.; Zeszotek, E.; Singer, T.P. The covalently-bound flavin of hepatic monoamine oxidase. 1. Isolation and sequence of a flavin peptide and evidence for binding at the 8alpha position. Eur. J. Biochem., 1971, 24(2), 321-327.
25. Boulton, A.A. Phenylethylaminergic modulation of catecholaminergic neurotransmission. Prog. Neuropsychopharmacol. Biol. Psychiatry., 1991, 15(2), 139-156.
26. Lasbennes, F.; Sercombe, R.; Seylaz, J. Monoamine oxidase activity in brain microvessels determined using natural and artificial substrates: relevance to the blood-brain barrier. J. Cereb. Blood Flow Metab., 1983, 3(4), 521-528.
27. Da Prada, M.; Zürcher, G.; Wüthrich, I.; Haefely, W.E. On tyramine, food, beverages and the reversible MAO inhibitor moclobemide. J. Neural Transm. Suppl., 1988, 26, 31-56.
28. Inoue, H.; Castagnoli, K.; Van Der Schyf, C.; Mabic, S.; Igarashi, K.; Castagnoli, N., Jr. Species-dependent differences in monoamine oxidase A and B-catalysed oxidation of various C4 substituted 1-methyl-4-phenyl-1,2,3, 6-tetrahydropyridinyl derivatives. J. Pharmacol. Exp. Ther., 1999, 291(2), 856-864.
29. Weyler, W.; Salach, J.I. Purification and properties of mitochondrial monoamine oxidase type A from human placenta. J. Biol. Chem., 1985, 260(24), 13199-13207.
30. Saura, J.; Nadal, E.; Van den Berg, B.; Vila, M,; Bombi, J.A.; Mahy, N. Localization of monoamine oxidases in human peripheral tissues. Life Sci., 1996, 59(16), 1341-1349.
31. Westlund, K.N.; Denney, R.M.; Kochersperger, L.M.; Rose, R.M.; Abell, C.W. Distinct monoamine oxidase A and B populations in primate brain. Science, 1985, 230(4722), 181-183.
32. Thorpe, L.W.; Westlund, K.N.; Kochersperger, L.M.; Abell, C.W.; Denney, R.M. Immunocytochemical localization of monoamine oxidases A and B in human peripheral tissues and brain. J. Histochem. Cytochem., 1987, 35(1), 23-32.
33. Fowler, C.J.; Wiberg, A.; Oreland, L.; Marcusson, J.; Winblad, B. The effect of age on the activity and molecular properties of human brain monoamine oxidase. J. Neural Transm., 1980, 49(1-2),1-20.
34. Kalaria, R.N.; Mitchell, M.J.; Harik, S.I. Monoamine oxidases of the human brain and liver. Brain, 1988, 111, 1441-1451.
35. Riachi, N.J.; Harik, S.I. Monoamine oxidases of the brains and livers of macaque and cercopithecus monkeys. Exp. Neurol., 1992, 115(2), 212-217.
36. Collins, G.G.; Sandler, M.; Williams, E.D.; Youdim, M.B. Multiple forms of human brain mitochondrial monoamine oxidase. Nature., 1970, 225(5235), 817-820.
37. Nicotra, A.; Pierucci, F.; Parvez, H.; Senatori, O. Monoamine oxidase expression during development and aging. Neurotoxicology, 2004, 25(1-2), 155-165.
38. Fowler, J.S.; Volkow, N.D.; Wang, G.J.; Logan, J.; Pappas, N.; Shea, C.; MacGregor, R. Age-related increases in brain monoamine oxidase B in living healthy human subjects. Neurobiol. Aging, 1997, 18(4), 431-435.
39. Levitt, P.; Pintar, J.E.; Breakefield, X.O. Immunocytochemical demonstration of monoamine oxidase B in brain astrocytes and serotonergic neurons. Proc. Natl. Acad. Sci. USA, 1982, 79(20), 6385-6389.
40. Fowler, J.S.; Logan, J.; Volkow, N.D.; Wang, G.J.; MacGregor, R.R.; Ding. Y.S. Monoamine oxidase: radiotracer development and human studies. Methods, 2002, 27(3), 263-277.
41. Riederer, P.; Lachenmayer, L.; Laux, G. Clinical applications of MAO-inhibitors. Curr. Med. Chem., 2004, 11(15), 2033-2043.
42. Zisook, S.; Braff, D.L.; Click, M.A. Monoamine oxidase inhibitors in the treatment of atypical depression. J. Clin. Psychopharmacol., 1985, 5(3), 131-137.
43. Fernandez, H.H.; Chen, J.J. Monoamine oxidase-B inhibition in the treatment of Parkinson's disease. Pharmacotherapy, 2007, 27(12 Pt 2), 174S-185S.
44. Finberg, J.P.; Wang, J.; Bankiewicz, K.; Harvey-White, J.; Kopin, I.J.; Goldstein, D.S. Increased striatal dopamine production from L-DOPA following selective inhibition of monoamine oxidase B by R(+)-N-propargyl-1-aminoindan (rasagiline) in the monkey. J. Neural Transm. Suppl., 1998, 52, 279-285.
45. Di Monte, D.A.; DeLanney, L.E.; Irwin, I.; Royland, J.E.; Chan, P.; Jakowec, M.W.; Langston, J.W. Monoamine oxidase-dependent metabolism of dopamine in the striatum and substantia nigra of L-DOPA-treated monkeys. Brain Res., 1996, 738(1), 53-59.
46. Shoulson, I.; Oakes, D.; Fahn, S.; Lang, A.; Langston, J.W.; LeWitt, P.; Olanow, C.W.; Penney, J.B.; Tanner, C.; Kieburtz, K.; Rudolph, A.; Parkinson Study Group. Impact of sustained deprenyl (selegiline) in levodopa-treated Parkinson's disease: a randomized placebo-controlled extension of the deprenyl and tocopherol antioxidative therapy of parkinsonism trial. Ann. Neurol., 2002, 51(5), 604-612.
47. Pålhagen, S.; Heinonen, E.H.; Hägglund, J.; Kaugesaar, T.; Kontants, H.; Mäki-Ikola, O.; Palm, R.; Turunen, J. Selegiline delays the onset of disability in de novo parkinsonian patients. Swedish Parkinson Study Group. Neurology, 1998, 51(2), 520-525.
48. Finberg, J.P.; Lamensdorf, I.; Armoni, T. Modification of dopamine release by selective inhibitors of MAO-B. Neurobiology (Bp), 2000, 8(2), 137-142.
49. Gesi, M.; Santinami, A.; Ruffoli, R.; Conti, G.; Fornai F. Novel aspects of dopamine oxidative metabolism (confounding outcomes take place of certainties). Pharmacol. Toxicol., 2001, 89, 217-224.
50. Fornai, F.; Giorgi, F.S.; Bassi, L.; Ferrucci, M.; Alessandrì, M.G.; Corsini, G.U. Modulation of dihydroxyphenylacetaldehyde extracellular levels in vivo in the rat striatum after different kinds of pharmacological treatment. Brain Res., 2000, 861, 126-134.
51. Marchitti, S.A.; Deitrich, R.A.; Vasiliou, V. Neurotoxicity and metabolism of the catecholamine-derived 3,4-dihydroxyphenylacetaldehyde and 3,4- dihydroxyphenylglycolaldehyde: the role of aldehyde dehydrogenase. Pharmacol. Rev., 2007, 59, 125-150.
52. Lamensdorf, I.; Eisenhofer, G.; Harvey-White, J.; Nechustan, A.; Kirk, K.; Kopin, I.J.; 3,4-Dihydroxyphenylacetaldehyde potentiates the toxic effects of metabolic stress in PC12 cells. Brain Res., 2000, 868(2), 191-201.
53. Burke, W.J.; Kumar, V.B.; Pandey, N.; Panneton, W.M.; Gan, Q.; Franko, M.W.; O'Dell, M.; Li, S.W.; Pan, Y.; Chung, H.D.; Galvin, J.E. Aggregation of alpha-synuclein by DOPAL, the monoamine oxidase metabolite of dopamine. Acta Neuropathol., 2008, 115(2), 193-203.
54. Grünblatt, E.; Mandel, S.; Jacob-Hirsch, J.; Zeligson, S.; Amariglo, N.; Rechavi, G.; Li, J.; Ravid, R.; Roggendorf, W.; Riederer, P.; Youdim, M.B. Gene expression profiling of parkinsonian substantia nigra pars compacta; alterations in ubiquitin-proteasome, heat shock protein, iron and oxidative stress regulated proteins, cell adhesion/cellular matrix and vesicle trafficking genes. J. Neural Transm., 2004, 111(12), 1543-1573.
55. Riederer, P.; Sofic, E.; Rausch, W.D.; Schmidt, B.; Reynolds, G.P.; Jellinger, K.; Youdim, M.B. Transition metals, ferritin, glutathione, and ascorbic acid in parkinsonian brains. J. Neurochem., 1989, 52(2), 515-520.
56. Mallajosyula, J.K.; Kaur, D.; Chinta, S.J.; Rajagopalan, S.; Rane, A.; Nicholls, D.G.; Di Monte, D.A.; Macarthur, H.; Andersen, J.K. MAO-B elevation in mouse brain astrocytes results in Parkinson's pathology. PLoS One, 2008, 3(2), e1616.
57. The Parkinson study group. Effect of lazabemide on the progression of disability in early Parkinson's disease. Ann. Neurol., 1996, 40(1), 99-107.
58. Pålhagen, S.; Heinonen, E.; Hägglund, J.; Kaugesaar, T.; Mäki-Ikola, O.; Palm, R. Swedish Parkinson Study Group. Selegiline slows the progression of the symptoms of Parkinson disease. Neurology, 2006, 66(8), 1200-1206.
59. Stocchi, F.; Vacca, L.; Grassini, P.; De Pandis, M.F.; Battaglia, G.; Cattaneo, C.; Fariello, R.G. Symptom relief in Parkinson disease by safinamide: Biochemical and clinical evidence of efficacy beyond MAO-B inhibition. Neurology, 2006, 67(7 Suppl 2), S24-S29.
60. Binda, C.; Wang, J.; Pisani, L.; Caccia, C.; Carotti, A.; Salvati, P.; Edmondson, D.E.; Mattevi, A. Structures of human monoamine oxidase B complexes with selective noncovalent inhibitors: safinamide and coumarin analogs. J. Med. Chem., 2007, 50(23), 5848-5852.
61. Chen, J.F.; Steyn, S.; Staal, R.; Petzer, J.P.; Xu, K.; Van Der Schyf, C.J.; Castagnoli, K.; Sonsalla, P.K.; Castagnoli, N., Jr.; Schwarzschild, M.A. 8-(3-Chlorostyryl)caffeine may attenuate MPTP neurotoxicity through dual actions of monoamine oxidase inhibition and A2A receptor antagonism. J. Biol. Chem., 2002, 277(39), 36040-36044.
62. Chen, J.F.; Xu, K.; Petzer, J.P.; Staal, R.; Xu, Y.H.; Beilstein, M.; Sonsalla, P.K.; Castagnoli, K.; Castagnoli, N., Jr.; Schwarzschild, M.A. Neuroprotection by caffeine and A2A adenosine receptor inactivation in a model of Parkinson's disease. J. Neurosci., 2001, 21(10), RC143.
63. Strydom, B.; Malan, S.F.; Castagnoli, N., Jr.; Bergh, J.J.; Petzer, J.P. Inhibition of monoamine oxidase by 8-benzyloxycaffeine analogues. Bioorg. Med. Chem., 2010, 18(3), 1018-1028.
64. Strydom, B.; Bergh, J.J.; Petzer, J.P. 8-Aryl- and alkyloxycaffeine analogues as inhibitors of monoamine oxidase. Eur. J. Med. Chem., 2011, 46(8), 3474-3485.
65. Binda, C.; Aldeco, M.; Geldenhuys, W.J.; Tortorici, M.; Mattevi, A.; Edmondson, D.E. Molecular insights into human monoamine oxidase B inhibition by the glitazone antidiabetes drugs. ACS Med. Chem. Lett., 2011, 3(1), 39-42.
66. Jacobson, K.A.; Gallo-Rodriguez, C.; Melman, N.; Fischer, B.; Maillard, M.; Van Bergen, A.; Van Galen, P.J.; Karton, Y. Structure-activity relationships of 8-styrylxanthines as A2- selective adenosine antagonists. J. Med. Chem., 1993, 36(10), 1333-1342.
67. Xu, K.; Bastia, E.; Schwarzschild, M. Therapeutic potential of adenosine A2A receptor antagonists in Parkinson's disease. Pharmacol. Ther., 2005, 105, 267-310.
68. Pinna, A.; Wardas, J.; Simola, N.; Morelli, M. New therapies for the treatment of Parkinson's disease: adenosine A2A receptor antagonists. Life Sci., 2005, 77, 3259-3267.
69. Morelli, M.; Di Paolo, T.; Wardas, J.; Calon, F.; Xiao, D.; Schwarzschild, M.A. Role of adenosine A2A receptors in parkinsonian motor impairment and l-DOPA-induced motor complications. Prog. Neurobiol., 2007, 83, 293-309.
70. Jarvis, M.F.; Williams, M. Direct autoradiographic localization of adenosine A2 receptors in the rat brain using the A2-selective agonist, [3H]CGS 21680. Eur. J. Pharmacol., 1989, 168, 243-246.
71. Schiffmann, S.N.; Jacobs, O.; Vanderhaeghen, J.J. Striatal restricted adenosine A2 receptor (RDC8) is expressed by enkephalin but not by substance P neurons: an in situ hybridization histochemistry study. J. Neurochem., 1991, 57, 1062-1067.
72. Fink, J.S.; Weaver, D.R.; Rivkees, S.A.; Peterfreund, R.A.; Pollack, A.E.; Adler, E.M.; Reppert, S.M. Molecular cloning of the rat A2 adenosine receptor: selective co-expression with D2 dopamine receptors in rat striatum. Brain Res. Mol. Brain Res., 1992, 14(3), 186-195.
73. Ferré, S.; Fredholm, B.B.; Morelli, M.; Popoli, P.; Fuxe, K. Adenosine-dopamine receptorreceptor interactions as an integrative mechanism in the basal ganglia. Trends Neurosci., 1997, 20, 482-487.
74. Ferré, S.; Von Euler, G.; Johansson, B.; Fredholm, B.B.; Fuxe, K. Stimulation of highaffinity adenosine A2 receptors decreases the affinity of dopamine D2 receptors in rat striatal membranes. Proc. Natl. Acad. Sci. USA, 1991, 88, 7238-7241.
75. Ferré, S.; O'Connor, W.T.; Fuxe, K.; Ungerstedt, U. The striopallidal neuron: a main locus for adenosine-dopamine interactions in the brain. J. Neurosci., 1993, 13, 5402-5406.
76. Bibbiani, F.; Oh, J.D.; Petzer, J.P.; Castagnoli, N., Jr.; Chen, J.F.; Schwarzschild, M.A.; Chase, T.N. A2A antagonist prevents dopamine agonist-induced motor complications in animal models of Parkinson's disease. Exp. Neurol., 2003, 184(1), 285-294.
77. Bara-Jimenez, W.; Sherzai, A.; Dimitrova, T.; Favit, A.; Bibbiani, F.; Gillespie, M.; Morris, M.J.; Mouradian, M.M.; Chase, T.N. Adenosine A2A receptor antagonist treatment of Parkinson's disease. Neurology, 2003, 61(3), 293-296.
78. Lundblad, M.; Vaudano, E.; Cenci, M.A. Cellular and behavioural effects of the adenosine A2A receptor antagonist KW-6002 in a rat model of l-DOPA-induced dyskinesia. J. Neurochem., 2003, 84, 1398-1410.
79. Fenu, S.; Pinna, A.; Ongini, E.; Morelli, M. Adenosine A2A receptor antagonism potentiates L-DOPA-induced turning behaviour and c-fos expression in 6-hydroxydopamine-lesioned rats. Eur. J. Pharmacol., 1997, 321, 143-147.
80. Kanda, T.; Jackson, M.J.; Smithm L.A.; Pearce, R.K.; Nakamura, J.; Kase, H.; Kuwana, Y.; Jenner, P. Adenosine A2A antagonist: a novel antiparkinsonian agent that does not provoke dyskinesia in parkinsonian monkeys. Ann. Neurol., 1998, 43(4), 507-513.
81. Grondin, R.; Bédard, P.J.; Hadj Tahar, A.; Grégoire, L.; Mori, A.; Kase, H. Antiparkinsonian effect of a new selective adenosine A2A receptor antagonist in MPTPtreated monkeys. Neurology, 1999, 52, 1673-1677.
82. Schwarzschild, M.A.; Agnati, L.; Fuxe, K.; Chen, J.F.; Morelli, M. Targeting adenosine A2A receptors in Parkinson's disease. Trends Neurosci., 2006, 29, 647-654.
83. Ascherio, A.; Zhang, S.M.; Hernán, M.A.; Kawachi, I.; Colditz, G.A.; Speizer, F.E.; Willett, W.C. Prospective study of caffeine consumption and risk of Parkinson's disease in men and women. Ann. Neurol., 2001, 50(1), 56-63.
84. Ross, G.W.; Abbott, R.D.; Petrovitch, H.; Morens, D.M.; Grandinetti, A.; Tung, K.H.; Tanner, C.M.; Masaki, K.H.; Blanchette, P.L.; Curb, J.D.; Popper, J.S.; White, L.R. Association of coffee and caffeine intake with the risk of Parkinson disease. JAMA, 2000, 283(20), 2674-2679.
85. Ikeda, K.; Kurokawa, M.; Aoyama, S.; Kuwana, Y. Neuroprotection by adenosine A2A receptor blockade in experimental models of Parkinson's disease. J. Neurochem., 2002, 80, 262-270.
86. Pretorius, J.; Malan, S.F.; Castagnoli, N., Jr.; Bergh, J.J.; Petzer, J.P. Dual inhibition of monoamine oxidase B and antagonism of the adenosine A2A receptor by (E,E)-8-(4-phenylbutadien-1-yl)caffeine analogues. Bioorg. Med. Chem., 2008, 16(18), 8676-8684.
87. Müller, C.E.; Geis, U.; Hipp, J.; Schobert, U.; Frobenius, W.; Pawłowski, M.; Suzuki, F.; Sandoval-Ramírez, J. Synthesis and structure-activity relationships of 3,7-dimethyl-1- propargylxanthine derivatives, A2A-selective adenosine receptor antagonists. J. Med. Chem., 1997, 40(26), 4396-4405.
88. Petzer, J.P.; Steyn, S.; Castagnoli, K.P.; Chen, J.F.; Schwarzschild, M.A.; Van der Schyf, C.J.; Castagnoli, N. Inhibition of monoamine oxidase B by selective adenosine A2A receptor antagonists. Bioorg. Med. Chem., 2003, 11(7), 1299-1310.
89. Shimada, J.; Koike, N.; Nonaka, H.; Shiozaki, S.; Yanagawa, K.; Kanda, T.; Kobayashi, H.; Ichimura, M.; Nakamura, J.; Kase, H.; Suzuki, F. Adenosine A2A antagonists with potent anti-cataleptic activity. Bioorg. Med. Chem. Lett., 1997, 18, 2349-2352.
90. Giasson, B.I.; Duda, J.E.; Murray, I.V.; Chen, Q.; Souza, J.M.; Hurtig, H.I.; Ischiropoulos, H.; Trojanowski, J.Q.; Lee, V.M. Oxidative damage linked to neurodegeneration by selective alpha-synuclein nitration in synucleinopathy lesions. Science, 2000, 290(5493), 985-589.
91. Zecca, L.; Youdim, M.B.; Riederer, P.; Connor, J.R.; Crichton, R.R. Iron, brain ageing and neurodegenerative disorders. Nat. Rev. Neurosci., 2004, 5(11), 863-873.
92. Gal, S.; Zheng, H.; Fridkin, M.; Youdim, M.B. Novel multifunctional neuroprotective iron chelator-monoamine oxidase inhibitor drugs for neurodegenerative diseases. In vivo selective brain monoamine oxidase inhibition and prevention of MPTP-induced striatal dopamine depletion. J. Neurochem., 2005, 95(1), 79-88.
93. Zheng, H.; Weiner, L.M.; Bar-Am, O.; Epsztejn, S.; Cabantchik, Z.I.; Warshawsky, A.; Youdim, M.B.; Fridkin, M. Design, synthesis, and evaluation of novel bifunctional ironchelators as potential agents for neuroprotection in Alzheimer's, Parkinson's, and other neurodegenerative diseases. Bioorg. Med. Chem., 2005, 13(3), 773-783.
94. Dexter, D.T.; Statton, S.A.; Whitmore, C.; Freinbichler, W.; Weinberger, P.; Tipton, K.F.; Della Corte, L.; Ward, R.J.; Crichton, R.R. Clinically available iron chelators induce neuroprotection in the 6-OHDA model of Parkinson's disease after peripheral administration. J. Neural Transm., 2011, 118(2), 223-231.
95. Youdim, M.B.; Stephenson, G.; Ben Shachar, D. Ironing iron out in Parkinson's disease and other neurodegenerative diseases with iron chelators: a lesson from 6-hydroxydopamine and iron chelators, desferal and VK-28. Ann. N. Y. Acad. Sci. USA, 2004, 1012, 306-325.
96. Sofic, E.; Paulus, W.; Jellinger, K.; Riederer, P.; Youdim, M.B. Selective increase of iron in substantia nigra zona compacta of parkinsonian brains. J. Neurochem., 1991, 56(3), 978-982.
97. Dexter, D.T.; Wells, F.R.; Lees, A.J.; Agid, F.; Agid, Y.; Jenner, P.; Marsden, C.D. Increased nigral iron content and alterations in other metal ions occurring in brain in Parkinson's disease. J. Neurochem., 1989, 52(6), 1830-1836.
98. Petzer, A.; Harvey, B.H.; Wegener, G.; Petzer, J.P. Azure B, a metabolite of methylene blue, is a high-potency, reversible inhibitor of monoamine oxidase. Toxicol. Appl. Pharmacol., 2012, 258(3), 403-409.
99. Brown, C.; Taniguchi, G.; Yip, K. The monoamine oxidase inhibitor-tyramine interaction. J. Clin. Pharmacol., 1989, 29(6), 529-532.
100. Costa, F.H.; Rosso, A.L.; Maultasch, H.; Nicaretta, D.H.; Vincent, M.B. Depression in Parkinson's disease: diagnosis and treatment. Arq. Neuropsiquiatr., 2012, 70(8), 617-620.
101. Flockhart, D.A. Dietary restrictions and drug interactions with monoamine oxidaseinhibitors: an update. J. Clin. Psychiatry., 2012, 73, Suppl 1:17-24.
102. Zesiewicz, T.A.; Hauser, R.A. Monoamine oxidase inhibitors. In Parkinson's disease:diagnosis and clinical management; Factor, S.A., Weiner, W.J., Eds.; Demos Medical Publishing: New York, 2002; pp 365 378.
103. Ramsay, R.R.; Dunford, C.; Gillman, P.K. Methylene blue and serotonin toxicity:inhibition of monoamine oxidase A (MAO A) confirms a theoretical prediction. Br. J. Pharmacol., 2007, 152(6), 946-951.
104. Stanford, S.C.; Stanford, B.J.; Gillman, P.K. Risk of severe serotonin toxicity following coadministration of methylene blue and serotonin reuptake inhibitors: an update on a case report of post-operative delirium. J. Psychopharmacol., 2010, 24, 1433-1438.
105. Bonnet, U. Moclobemide: therapeutic use and clinical studies. CNS Drug. Rev., 2003, 9(1), 97-140.
106. Wu, M.L.; Deng, J.F. Fatal serotonin toxicity caused by moclobemide and fluoxetine overdose. Chang. Gung. Med. J., 2011, 34(6), 644-649.
107. Fowler, J.S.; Volkow, N.D.; Logan, J.; Wang, G.J.; MacGregor, R.R.; Schlyer, D.; Wolf, A.P.; Pappas, N.; Alexoff, D.; Shea, C.; Dorflinger, E.; Yoo, K.; Fazzini, E.; Patlak, C. Slow recovery of human brain MAO B after L-deprenyl (Selegeline) withdrawal. Synapse, 1994, 18(2), 86-93.
108. Hubálek, F.; Binda, C.; Khalil, A.; Li, M.; Mattevi, A.; Castagnoli, N.; Edmondson, D.E. Demonstration of isoleucine 199 as a structural determinant for the selective inhibition of human monoamine oxidase B by specific reversible inhibitors. J. Biol. Chem., 2005, 280(16), 15761-15766.
109. Anglade, P.; Vyas, S.; Javoy-Agid, F.; Herrero, M.T.; Michel, P.P.; Marquez, J.; Mouatt-Prigent, A.; Ruberg, M.; Hirsch, E.C.; Agid, Y. Apoptosis and autophagy in nigral neurons of patients with Parkinson's disease. Histol. Histopathol., 1997, 12(1), 25-31.
110. Marshall, K.; Daniel, S.E.; Cairns, N.; Jenner, P.; Halliwell, B. Upregulation of the antiapoptotic protein Bcl-2 may be an early event in neurodegeneration: studies on Parkinson's and incidental Lewy body disease. Biochem. Biophys. Res. Commun., 1997, 240, 84-87.
111. Hartmann, A.; Michel, P.P.; Troadec, J.D.; Mouatt-Prigent, A.; Faucheux, B.A.; Ruberg, M.; Agid, Y.; Hirsch, E.C. Is Bax a mitochondrial mediator in apoptotic death of dopaminergic neurons in Parkinson's disease? J. Neurochem., 2001, 76(6), 1785-1793.
112. Mogi, M.; Togari, A.; Kondo, T.; Mizuno, Y.; Komure, O.; Kuno, S.; Ichinose, H.; Nagatsu, T. Caspase activities and tumor necrosis factor receptor R1 (p55) level are elevated in the substantia nigra from parkinsonian brain. J. Neural Transm., 2000, 107(3), 335-341.
113. Hartmann, A.; Troadec, J.D.; Hunot, S.; Kikly, K.; Faucheux, B.A.; Mouatt-Prigent, A.; Ruberg, M.; Agid, Y.; Hirsch E.C. Caspase-8 is an effector in apoptotic death of dopaminergic neurons in Parkinson's disease, but pathway inhibition results in neuronal necrosis. J. Neurosci., 2001, 21(7), 2247-2255.
114. Maruyama, W.; Akao, Y.; Carrillo, M.C.; Kitani, K.; Youdim, M.B.; Naoi, M. Neuroprotection by propargylamines in Parkinson's disease: suppression of apoptosis and induction of prosurvival genes. Neurotoxicol. Teratol., 2002, 24(5), 675-682.
115. Blandini, F. Neuroprotection by rasagiline: A new therapeutic approach to Parkinson's disease? CNS Drug Rev., 2005, 11(2), 183-194.
116. Edmondson, D.E.; Mattevi, A.; Binda, C.; Li, M.; Hubálek, F. Structure and mechanism of monoamine oxidase. Curr. Med. Chem., 2004, 11(15), 1983-1993.
117. Binda, C.; Hubálek, F.; Li, M.; Herzig, Y.; Sterling, J.; Edmondson, D.E.; Mattevi, A. Binding of rasagiline-related inhibitors to human monoamine oxidases. a kinetic and crystallographic analysis. J. Med. Chem., 2005, 48(26), 8148-8154.
118. Maruyama, W.; Akao, Y.; Youdim, M.B.; Naoi, M. Neurotoxins induce apoptosis in dopamine neurons: protection by N-propargylamine-1(R)- and (S)-aminoindan, rasagiline and TV1022. J. Neural Transm. Suppl., 2000, (60), 171-186.
119. Lemasters, J.J.; Nieminen, A.L.; Qian, T.; Trost, L.C.; Elmore, S.P.; Nishimura, Y.; Crowe, R.A.; Cascio, W.E.; Bradham, C.A.; Brenner, D.A.; Herman, B. The mitochondrial permeability transition in cell death: a common mechanism in necrosis, apoptosis and autophagy. Biochim. Biophys. Acta, 1998, 1366(1-2), 177-196.
120. Bar-Am, O.; Yogev-Falach, M.; Amit, T.; Sagi, Y.; Youdim, M.B. Regulation of protein kinase C by the anti-Parkinson drug, MAO-B inhibitor, rasagiline and its derivatives, in vivo. J. Neurochem., 2004, 89(5), 1119-1125.
121. Youdim, M.B.; Weinstock, M. Molecular basis of neuroprotective activities of rasagiline and the anti-Alzheimer drug TV3326 [(N-propargyl-(3R)aminoindan-5-YL)-ethyl methyl carbamate]. Cell. Mol. Neurobiol., 2001, 21(6), 555-573.
122. Mandel, S.; Weinreb, O.; Amit, T.; Youdim, M.B. Mechanism of neuroprotective action of the anti-Parkinson drug rasagiline and its derivatives. Brain Res. Brain Res. Rev., 2005, 48(2), 379-387.
123. Youdim, M.B.; Wadia, A.; Tatton, W.; Weinstock, M. The anti-Parkinson drug rasagiline and its cholinesterase inhibitor derivatives exert neuroprotection unrelated to MAO inhibition in cell culture and in vivo. Ann. N. Y. Acad. Sci. USA, 2001, 939, 450-458.
124. Gottfries, C.G.; Neurochemical aspects on aging and diseases with cognitive impairment, J. Neurosci. Res., 2009, 27, 541-547.
125. Meltzer, C.C.; Smith, G.; Dekosky, S.T.; Pollock, B.G.; Mathis, C.A.; Moore, R.Y.; Kupfer, D.J.; Reynolds, C.F. Serotonin in aging, late-life depression, and Alzheimer's disease: The emerging role of functional imaging', Neuropsychopharmacology, 1998, 18, 407-430.
126. Fink, D.M.; Palermo, M.G.; Bores, G.M.; Huger, F.P.; Kurys, B.E.; Merriman, M.C.; Olsen, G.E.; Petko, W.; O'Malley, G.J. Imino 1,2,3,4-tetrahydrocyclopent[b]indole carbamates as dual inhibitors of acetylcholine esterase and monoamine oxidase. Bioorg. Med. Chem. Lett., 1996, 6, 625-630.
127. Hilgert, M.; Nöldner, M.; Chatterjee, S.S.; Klein, J. KA-672 inhibits rat brain acetylcholinesterase in vitro but not in vivo. Neurosci. Lett., 1999, 263, 193-196.
128. Gnerre, C.; Catto, M.; Leonetti, F.; Weber, P.; Carrupt, P.A.; Altomare, C.; Carotti, A.; Testa, B. Inhibition of monoamine oxidases by functionalized coumarin derivatives:biological activities, QSARs, and 3D-QSARs. J. Med. Chem., 2000, 43, 4747-4758.
129. Bruhlmann, C.; Ooms, F.; Carrupt, P.A.; Testa, B.; Catto, M.; Leonetti, F.; Altomare, C.; Carotti, A. Coumarin derivatives as dual inhibitors of acetylcholinesterase and monoamine oxidase. J. Med. Chem., 2001, 44, 3195-3198.
130. Viña, D.; Matos, M.J.; Yáñez, M.; Santana, L.; Uriarte, E. 3-Substituted coumarins as dual inhibitors of AchE and MAO for the treatment of Alzheimer's disease. Med. Chem. Comm., 2012, 3, 213-218.
131. Gökhan, N.; Yesilada, A.; Uçar, G.; Erol, K.; Bilgin, AA. 1-N-Substituted thiocarbamoyl-3- phenyl-5-thienyl-2-pyrazolines: synthesis and evaluation as MAO inhibitors, Archiv der Pharmazie., 2003, 336, 362-371.
132. Uçar, G.; Gökhan, N.; Yesilada, A.; Bilgin, A.A. 1-N-Substituted thiocarbamoyl-3-phenyl-5-thienyl-2-pyrazolines: A novel cholinesterase and selective monoamine oxidase B inhibitors for the treatment of Parkinson's and Alzheimer's diseases. Neurosci. Lett., 2005, 382, 327-331.
133. Martin, I.N.; Woodward, J.J.; Winter, M.B.; Beeson, W.T.; Marletta, M.A. Design and synthesis of C5 Methylated L-arginine analogues as active site probes for nitric oxide synthase. J. Am. Chem. Soc., 2007, 129, 12563-12570.
134. Dawson, V.L.; Dawson, T.M.; Lomdon, E.D.; Bredt, D.S.; Snyder, S.H. Nitric oxide mediates glutamate neurotoxicicty in primary cortical cultures. Proc. Natl. Acad. Sci., 1991, 88, 6368-6371.
135. Knowles, R.G.; Moncada, S. Nitric oxide synthases in mammals. Biochem. J. 1994, 298, 249-258.
136. Cary, S.P.L.; Winger, J.A.; Derbyshire, E.R.; Marletta, M.A. Nitric oxide signaling: no longer simply on or off. Trends. Biochem. Sci., 2006, 31, 231-239.
137. Hoffman, B,B.; Taylor P. Goodman and Gilman's. The pharmacological basis of therapeutics. Chapter 6: Neurotransmission. New York: McGraw-Hill. 2001, 148p.
138. Roman, L.J.; Mattasek, P.; Masters, B.S.S. Intrinsic and extrinsic modulation of nitric oxide synthase activity. Chem. Rev., 2002, 102, 1179-1189.
139. Marletta, M.A. Nitric oxide synthase structure and mechanism. J. Biol. Chem., 1993, 268, 12231-12234.
140. Steur, D.J. Mammalian nitric oxide synthase. Biochimica et Biophysica ACTA/General Subjects, 1999, 1411, 217-230.
141. Alderton, W.K.; Cooper, C.E.; Knowles, R.G. Nitric oxide synthases: structure function and inhibition. Biochem. J., 2001, 357, 593-615.
142. Kerwin, J.F.; Lancaster, J.R.; Feldamn, P.L. Nitric Oxide: A new paradigm for second messengers. J. Med. Chem., 1995, 38, 4343-4362.
143. Joubert, J.; Malan, S.F. Nitric Oxide Synthase (NOS) inhibitors: a patent review. Exp. Opin. Ther. Pat., 2011, 21, 537-560.
144. Boughton, S.N.K.; Tinker, A.C. Inhibitors of nitric oxide synthase in inflammatory arthritis. IDrugs, 1998, 1, 321-333.
145. Endres, M.; Laufs, U.; Liao, J.K.; Moskowitz, M.A. Targeting eNOS for stroke protection. Trends. Neurosci., 2004, 27, 283-289.
146. Braam, B.; Verhaar, M.C. Understanding eNOS for pharmacological modulation of endothelial function: a translational view. Curr. Pharm., 2007, 13, 1727-1740.
147. Larson, A.A.; Kovacs, K.J.; Cooper, J.C.; Kitto, K.F. Transient changes in the synthesis of nitric oxide result in long-term as well as short-term changes in acetic acid-induced writhing in mice. Pain, 2000, 86, 103-111.
148. Vallance, P.; Leiper, J. Blocking NO Synthesis: how, where and why? Nat. Rev. Drug. Discovery, 2002, 1, 939-950.
149. Wilcock, D.M.; Lewis, M.R.; Van Nostrand, W.E.; Davis, J.; Previti, M.L.; Gharkholonarehe, N.; Vitek, M.P.; Colton, C.A. Progression of amyloid pathology to Alzheimer's disease pathology in an amyloid precursor protein transgenic mouse model by removal of nitric oxide synthase 2. J. Neurosci., 2008, 28, 1537-1545.
150. Babbedge, R.C.; Bland-Ward, P.A.; Hart, S.L.; Moore, P.K. Inhibition of rat cerebellar nitric oxide synthase by 7-nitro indazole and related substituted indazoles. Br. J. Pharmcol. 1993, 1, 225-228.
151. Babu, B.R.; Griffith, O.W.; 1998. Design of the isoform-selective inhibitors of nitric oxide synthase. Curr. Opin. Chem.l Biol., 1998, 2, 491-500.
152. Pekiner, C.; Kelicen, P.; Uma, S.; Miwa, I. Two nitric oxide synthase inhibitors: pyridoxal aminoguanidine and 8-quinolinecarboxylic hydrazide selectively inhibit basal but not agoniststimulated release of nitric oxide in rat aorta. Pharmacol. Res., 2002, 46, 317-320.
153. Zhang, Z.G.; Reif, D.; MacDonald, W.X.; Tang, W.X.; Kamp, D.K.; Gentile, R.J.; Shakespeare, W.C.; Murray, R.J.; Chopp, M. ARL 17477, a potent and selective neuronal NOS inhibitor decreases infarct volume after transient middle cerebral artery occlusion in rats. J. Cereb. Blood. Flow. Metab., 1996, 16, 599-604.
154. Chan. P.H. Role of oxidants in ischemic brain damage. Stroke, 1996, 27, 1124-1129.
155. Samdani, A.F.; Dawson, T.M.; Dawson, V.L. Nitric oxide synthase in models of focal ischemia. Stroke., 1997, 28, 1283-1288.
156. Hall, E.D.; Braughler, J.M. Central nervous system trauma and stroke. II. Physiological and pharmacological evidence for involvement of oxygen radicals and lipid peroxidation. Free Radic. Biol. Med., 1986, 6, 303-313.
157. Beckman, J.S.; Beckman, T.W.; Chen, J.; Marshall, P.A.; Freeman, B.A. Apparent hydroxyl radical production by peroxynitrite: implications for endothelial injury from nitric oxide and superoxide. Proc. Natl. Acad. Sci. USA, 1990, 87, 1620-1624.
158. Sorrenti, V.; Di Giacomo, C.; Campisi, A.; Perez-Polo, J.R.; Vanella, A. Nitric oxide synthetase activity in cerebral post-ischemic reperfusion and effects of L-NG-nitroarginine and 7-nitroindazole on the survival, Neurochem. Res., 1999, 24, 861-866.
159. Escott, K.J.; Beech, J.S.; Haga, K.K.; Williams, S.C.R.; Meldrum, B.S.; Bath, P.M.W. Cerebroprotective effect of the nitric oxide synthase inhibitors, 1-(2-trifluoromethylphenyl) imidazole and 7-nitro indazole, after transient focal cerebral ischemia in the rat. J. Cereb. Blood. Flow. Metab., 1998, 18, 281-287.
160. Chalimoniuk, M.; Strosznajder, J. NMDA receptor-dependent nitric oxide and cGMP synthesis in brain hemispheres and cerebellum during reperfusion after transient forebrain ischemia in Gerbils: effect of 7-nitroindazole. J. Neurosci. Res., 1998, 54, 681-690.
161. Sorrenti, V.; Di Giacomo, C.; Renis, M.; Russo, A.; La Delfa, C.; Perez-Polo, J.R.; Vanella, A. Lipid peroxidation in rat cerebral cortex during post-ischemic reperfusion: effect of drugs with different molecular mechanisms. Drugs. Exp. Clin. Res., 1994, 20, 185-189.
162. Auvin, S.; Auguet, M.; Navet, E.; Harnett, J.J; Viossat, I.; Schulz, J.; Bigg, D.; Chabrier. P.E. Novel Inhibitors of Neuronal Nitric Oxide Synthase with Potent Antioxidant Properties. Bioorg. Med. Chem. Lett., 2003, 13, 209-212.
163. Sgaragli, G. P.; Valoti, M.; Gorelli, B.; Fusi, F.; Palmi, M.; Mantovani, P. Calcium antagonist and antiperoxidant properties of some hindered phenols. Br. J. Pharmacol., 1993, 110, 369.
164. Chabrier, P.E.; Auguet, M.; Spinnewyn, B.; Auvin, S.; Cornet, S.; Demerle-Pallardy, C.; Guilmard-Favre, C.; Marin, J.G.; Pignol, B.; Gillard-Roubert, V.; Roussillot-Charnet, C.; Schulz, J.; Viossat, I.; Bigg, D.; Moncada, S. BN 80933, a dual inhibitor of neuronal nitric oxide synthase and lipid peroxidation: a promising neuroprotective strategy. Proc. Natl. Acad. Sci. USA, 1999, 96, 10824-10829.
165. Ding-Zhou, L.; Marchand-Verrecchia, C.; Palmier, B.; Croci, N.; Chabrier, P.E.; Plotkine, M.; Margaill, I. Neuroprotective effects of (S)-N-[4-[4-[(3,4-dihydro6-hydroxy-2,5,7,8- tetramethyl-2H-1-benzopyran-2-yl)carbonyl]-1-piperazinyl]phenyl]-2-thiophenecarboximidamide (BN 80933), an inhibitor of neuronal nitric-oxide synthase and an antioxidant, in model of transient focal cerebral ischemia in mice. J. Pharmacol. Exp. Ther., 2003, 306, 588-594.
166. Salerno, L.; Modica, M.N.; Romeo, G.; Pittalà, V.; Siracusa, M.A.; Amato, M.E.; Acquaviva, R.; Di Giacomo, C.; Sorrenti, V. Novel inhibitors of nitric oxide synthase with antioxidant properties. Eur. J. Med. Chem., 2012, 49, 118-126.
167. Sorrenti, V.; Salerno, L.; Di Giacomo, C.; Acquaviva, R.; Siracusa, M.A. Vanella, A. Imidazole derivatives as antioxidants and selective inhibitors of nNOS. Nitric. Oxide, 2006, 14, 45-50.
168. Kemp, J.A.; Mckernan, R.M. NMDA receptor pathways as drug targets. Nat. Neurosci., 2002, 5, 1039-1042.
169. Mattson, M.P. Excitotoxic and excitoprotective mechanisms: abundant targets for the prevention and treatment of neurodegenerative disorders. Neuromol. Med., 2003, 3, 65-94.
170. Meldrum, B.; Garthwaite, J. Excitatory amino acid neurotoxicity and neurodegenerative disease. Trends. Pharmacol. Sci., 1990, 11, 379-387.
171. Alexi, T.; Borlogan, C.V.; Faull, R.L.M.; Williams, C.E.; Clark, R.G.; Gluckman, P.D.; Huges, P.E. Neuroprotective strategies for basal ganglia degeneration: Parkinson's and Huntington's diseases. Prog. Neurobiol., 2000, 60, 409-470.
172. Lipton, P. Ischemic cell death in brain neurons. Physiol. Rev., 1991, 79, 1431-568.
173. Cano-Abad, M.F.; Villarroya, M.; Garcia, A.G.; Gabilan, N.H.; Lopez, M.G. Calcium entry through L-type calcium channels causes mitochondrial disruption and chromaffin cell death. J. Biol. Chem., 2001, 276, 39695-39704.
174. Moncada, S.; Palmer, R.M.J.; Higgs, E.A. Biosynthesis of nitric oxide from L-arginine. A pathway for the regulation of cell function and communication. Biochem. Pharmacol., 1989, 38, 1709-1715.
175. Neuraxon, Inc. Substituted indole compounds having NOS inhibitory activity. US20060258721. 2006
176. Neuraxon, Inc. Substituted indole compounds having NOS inhibitory activity. WO2007063418. 2007
177. Neuraxon, Inc. 1,5 and 3,6-substituted indole compounds having NOS inhibitory activity. WO2007118314. 2007
178. Neuraxon, Inc. 3,5-Substituted indole compounds having NOS and norepinephrine reuptake inhibitory activity. WO2009062318. 2009
179. Neuraxon, Inc. Indole compounds and methods for treating visceral pain. WO2009062319. 2009.
180. Hevel, J.M.; Marletta, M.A. Nitric oxide synthase assays. Methods Enzymol., 1994, 133, 250-258.
181. Joubert, J.; Van Dyk, S.; Green, I.R.; Malan, S.F. Synthesis and evaluation of fluorescent heterocyclic aminoadamantanes as multifunctional neuroprotective agents. Bioorg. Med. Chem., 2011, 19, 3935-3944.
182. Joubert, J.; Geldenhuys, W.J.; Van der Schyf, C.J.; Oliver, D.W.; Kruger, H.; Govender, T.; Malan. S.F. Polycyclic cage structures as lipophilic scaffolds for neuro-active drugs. ChemMedChem., 2012, 7, 375-384.
183. Van der Schyf, C.J.; Squier, G.J.; Coetzee, W.A. Characterization of NGP 1-01, an aromatic polycyclic amine, as a calcium antagonist. Pharmacol. Res. Com., 1986, 18, 407-417.
184. Malan, S.F., Van der Walt, J.J.; Van der Schyf, C.J. Structure-activity relationships of polycyclic aromatic amines with calcium channel blocking activity. Archiv der Pharmazie., 2000, 333, 10-16.
185. Malan, S.F., Dyason, K. Wagenaar, B., Van der Walt, J.J.; Van der Schyf, C.J. The structure and ion channel activity of 6-benzylamino-3-hydroxyhexacyclo [6.5.0.0(3,7).0(4,12).0(5,10).0(9,13)]tridecane. Archiv der Pharmazie., 2003, 336, 127-133.
186. Joubert, J. ; Van Dyk, S. ; Green, I.R. ; Malan. S.F. Synthesis, evaluation and application of polycyclic fluorescent analogues as N-methyl-D-aspartate receptor and voltage gated calcium channel ligands. Eur. J. Med. Chem., 2011, 46, 5010-5020.
187. Van Der Schyf, C.J.; Youdim, M.B. Multifunctional drugs as neurotherapeutics. Neurother., 2009, 6, 1-201.
188. Joubert, J.; Van Dyk, S.; Malan, S.F. Fluorescent polycyclic ligands for nitric oxide synthase (NOS) inhibition. Bioorg. Med. Chem., 2008, 16, 8952-8958.
189. Xu, K.Y.; Huso, D.L.; Dawson, T.M.; Bredt, D.S.; Becker, L.C. Nitric oxide synthase in cardiac sarcoplasmic reticulum. Proc. Natl. Acad. Sci. USA, 1991, 96, 657-662.
190. Herraiz, T.; Aran, V.J.; Guillen, H. Nitroindazole compounds inhibit the oxidative activation of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridin (MPTP) neurotoxin to neurotoxic pyridinium cations by human monoamine oxidase (MAO). Free. Rad. Res., 2009, 43, 975-984.
191. Thomas, B, Saravanan, K.S., Mohanakumar, K.P. In vitro and in vivo evidences that antioxidant action contributes to the neuroprotective effects of the neuronal nitric oxide synthase and monoamine oxidase-B inhibitor, 7-nitroindazole. Neurochem. Int., 2008, 52, 990-1001.
192. Prins, L.H.A.; Petzer, J.P.; Malan, S.F. Synthesis and in vitro evaluation of pteridine analogues as monoamine oxidase B and nitric oxide synthase inhibitors. Bioorg. Med. Chem., 2009, 17, 7523-7530.
193. Crane, B.R.; Arvai, A.S.; Ghosh, D.K.; Wu, C.; Getzoff, E.D.; Stuehr, D.J.; Tainer, J.A. Structure of nitric oxide synthase oxygenase dimer with pterin and substrate. Science, 1998, 279, 2121-2126.
194. Chen, J.F.; Steyn, S.; Staal, R.; Petzer, J.P.; Xu, K.; Van der Schyf, C.J.; Castagnoli, K.; Sonsalla, P.K.; Castagnioli, N.; Schwarzschild, M.A. 8-(3-chlorostyryl)caffeine may attenuate MPTP neurotoxicity through dual actions of monoamine oxidase inhibition and A2A receptor antagonism. J. Biol. Chem., 2002, 277, 36040-36044.
195. Vlok, N.; Malan, S.F.; Castagnoli, N.; Bergh, J.J.; Petzer, J.P. Inhibition of monoamine oxidase B by analogues of the adenosine A2A receptor antagonist (E)-8-(3-chlorostyryl) caffeine (CSC). Bioorg. Med. Chem., 2006, 14, 3512-3521.
196. Balsa, D.; Fernández-Álvarez, E.; Tipton, K.F.; Unzeta, M. Inhibition of MAO by substituted tryptamine analogues. J. Neur. Trans. Supp., 1991, 32, 103-105.
197. Balsa, D.; Fernández-Álvarez, E.; Tipton, K.F.; Unzeta, M. Monoamine oxidase inhibitory potencies and selectivities of 2-[N-(2-propynyl)-aminomethyl]-1-methyl indole derivatives. Biochem. Soc. Trans., 1991, 19, 215-218.
198. Fernández-García, C.; Marco, J.L.; Fernández-Álvarez, E. Acetylenic and allenic derivatives of 2-(5-methoxy-1-methylindolyl) alkylamines: Synthesis and evaluation as selective inhibitors of the monoamine oxidases A and B. Eur. J. Med. Chem., 1992, 27, 909-918.
199. Morón, J.A.; Campillo, M.; Pérez, V.; Unzeta, M.; Pardo, L. Molecular determinants of MAO selectivity in a series of indolylmethylamine derivatives: Biological activities, 3DQSAR/ CoMFA analysis, and computational simulation of ligand recognition. J. Med. Chem., 2000, 43, 1684-1691.
200. Pérez, V.; Marco, J.L.; Fernández-Álvarez, E.; Unzeta, M. Relevance of a benzyloxy group in 2-indolyl methylamines in the selective MAO-B inhibition, Br. J. Pharmacol., 1991, 127, 869-876.
201. Bellik, L.; Dragoni, S.; Pessina, F.; Sanz, E.; Unzeta, M.; Valoti, M. Antioxidant properties of PF9601N, a novel MAO-B inhibitor: assessment of its ability to interact with reactive nitrose species. Acta. Biochim. Pol., 2010, 57, 235-239.
202. Pérez, V.; Unzeta, M. PF9601N [N-(2-propynyl)-2-(5-benzyloxyindolyl)methylamine], a new MAO-B inhibitor, attenuates MPTP induced depletion of striatal dopamine levels in C57/BL mice. Neurochem. Internat., 2003, 42, 221-229.
203. Sanz, E.; Quintana, A.; Battaglia, V.; Toninello, A.; Hidalgo, J.; Ambrosio, S.; Valoti, M.; Marco, J.L.; Tipton, K.F.; Unzeta, M. Anti-apoptotic effect of MAO-B inhibitor PF9601N [N-(2-propynyl)-2-(5-benzyloxyindolyl)methylamine] is mediated by p53 pathway inhibition in MPP+-treated SH-SY5Y human dopaminergic cells. J. Neurochem., 2008, 105, 2404-2417.
204. Aarsland, D.; Hutchinson, M.; Larsen, J.P. Cognitive, psychiatric and motor response to galantamine in Parkinson's disease with dementia. Int. J. Geriatr. Psychiatry, 2003, 18, 937-941.
205. Aarsland, D.; Laake, K.; Larsen, J.P.; Janvin, C. Donepezil for cognitive impairment in Parkinson's disease: a randomised controlled study. J. Neurol. Neurosurg. Psychiatry, 2002, 72, 708-712.
206. Giladi, N.; Shabtai, H.; Gurevich, T.; Benbunan, B.; Anca, M.; Korczyn, A.D. Rivastigmine (Exelon) for dementia in patients with Parkinson's disease. Acta. Neurol. Scand., 2003, 108, 368-373.
207. Leroi, I.; Brandt, J.; Reich, S. G.; Lyketsos, C.G.; Grill, S.; Thompson, R.; Marsh, L. Randomized placebo-controlled trial of donepezil in cognitive impairment in Parkinson's disease. Int. J. Geriatr. Psychiatry, 2004, 19, 1-8.
208. Ravina, B.; Putt, M.; Siderowf, A.; Farrar, J.T.; Gillespie, M.; Crawley, A.; Fernandez, H.H.; Trieschmann, M.M.; Reichwein, S.; Simuni, T. Donepezil for dementia in Parkinson's disease: a randomised, double blind, placebo controlled, crossover study. J. Neurol. Neurosurg. Psychiatry, 2005, 76, 934-939.
209. Linazasoro, G.; Lasa, A.; Van Blercom, N. Efficacy and safety of donepezil in the treatment of executive dysfunction in Parkinson disease: a pilot study. Clin. Neuropharmacol, 2005., 28, 176-178.
210. Sussman, J.L.; Harel, M.; Frolow, F.; Oefner, C.; Goldman, A.; Toker, L.; Silman, I. Atomic structure of acetylcholinesterase from Torpedo californica: a prototypic acetylcholine-binding protein. Science, 1991, 253, 872-879.
211. Ollis, D.L.; Cheah, E.; Cygler, M.; Dijkstra, B.; Frolow, F.; Franken, S.M.; Harel, M.; Remington, S.J.; Silman, I.; Schrag, J. The alpha/beta hydrolase fold. Protein Eng., 1992, 5, 197-211.
212. Cygler, M.; Schrag, J.D.; Sussman, J.L.; Harel, M.; Silman, I.; Gentry, M.K.; Doctor, B.P. Relationship between sequence conservation and three-dimensional structure in a large family of esterases, lipases, and related proteins. Protein Sci., 1993, 2, 366-382.
213. M. Harel, D.M. Quinn, H.K. Nair, I. Silman, J.L. Sussman, The X-ray structure of a transition state analog complex reveals the molecular origins of the catalytic power and substrate specificity of acetylcholinesterase. J. Am. Chem. Soc., 1996, 118, 2340-2346.
214. Knapp, M.J.; Knopman, D.S.; Solomon, P.R.; Pendlebury, W.W.; Davis, C.S.; Gracon, S.I. A 30-week randomized controlled trial of high-dose tacrine in patients with Alzheimer's disease. The Tacrine Study Group. JAMA, 1994, 271, 985-991.
215. Watkins, P.B.; Zimmerman, H.J.; Knapp, M.J.; Gracon, S.I.; Lewis, K.W. Hepatotoxic effects of tacrine administration in patients with Alzheimer's disease. JAMA, 1994, 271, 992-998.
216. Kasa, P.; Rakonczay, Z.; Gulya, K. The cholinergic system in Alzheimer's disease. Prog. Neurobiol, 1997, 52, 511-535.
217. Gualtieri, F.; Dei, S.; Manetti, D.; Romanelli, M.N.; Scapecchi, S.; Teodori, E. The medicinal chemistry of Alzheimer's and Alzheimer-like diseases with emphasis on the cholinergic hypothesis. Farmaco., 1995, 50, 489-503.
218. Yan, J.W.; Li, Y.P.; Ye, W.J.; Chen, S.B.; Hou, J.Q.; Tan, J.H.; Ou, T.M.; Li, D.; Gu, L.Q.; Huang, Z.S. Design, synthesis and evaluation of isaindigotone derivatives as dual inhibitors for acetylcholinesterase and amyloid beta aggregation. Bioorg. Med. Chem., 2012, 20, 2527-2534.
219. 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.
220. Camps, P.; Formosa, X.; Galdeano, C.; Munoz-Torrero, D.; Ramirez, L.; Gomez, E.; Isambert, N.; Lavilla, R.; Badia, A.; Clos, M. V.; Bartolini, M.; Mancini, F.; Andrisano, V.; Arce, M. P.; Rodriguez-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 betaamyloid- directed anti-Alzheimer compounds. J. Med. Chem., 2009, 52, 5365-5379.
221. Tang, H.; Zhao, L.Z.; Zhao, H. T.; Huang, S.L.; Zhong, S.M.; Qin, J.K.; Chen, Z.F.; Huang, Z.S.; Liang, H. Hybrids of oxoisoaporphine-tacrine congeners: novel acetylcholinesterase and acetylcholinesterase-induced beta-amyloid aggregation inhibitors. Eur. J. Med. Chem., 2011, 46, 4970-4979.
222. Luo, J.; Li, W.; Zhao, Y.; Fu, H.; Ma, D.L.; Tang, J.; Li, C.; Peoples, R.W.; Li, F.; Wang, Q.; Huang, P.; Xia, J.; Pang, Y.; Han, Y. 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., 2010, 285, 19947-19958.
223. Lanctôt, K.L.; Rajaram, R.D.; Herrmann, N. Therapy for Alzheimer's Disease: How Effective are Current Treatments? Ther. Adv. Neurol. Disord., 2009, 2(3), 163-80.
224. Moriguchi, S.; Marszalec, W.; Zhao, X.; Yeh, J.Z.; Narahashi, T. Mechanism of action of galantamine on N-methyl-D-aspartate receptors in rat cortical neurons. J. Pharmacol. Exp. Ther., 2004, 310(3), 933-42.
225. Arias, E.; Alés, E.; Gabilan, N.H.; Cano-Abad, M.F.; Villarroya, M.; García, A.G.; López, M.G. Galantamine prevents apoptosis induced by beta-amyloid and thapsigargin:involvement of nicotinic acetylcholine receptors. Neuropharm., 2004, 46(1), 103-14.
226. Lorrio, S.; Sobrado, M.; Arias, E.; Roda, J.M.; García, A.G.; López, M.G. Galantamine postischemia provides neuroprotection and memory recovery against transient global cerebral ischemia in gerbils. J. Pharmacol. Exp. Ther., 2007, 322(2), 591-599.
227. Ezoulin, M.J.; Ombetta, J.E.; Dutertre-Catella, H.; Warnet, J.M.; Massicot, F. Antioxidative properties of galantamine on neuronal damage induced by hydrogen peroxide in SK-N-SH cells. Neurotoxicology, 2008, 29(2), 270-277.
228. Bachurin, S.; Bukatina, E.; Lermontova, N.; Tkachenko, S.; Afanasiev, A.; Grigoriev, V.; Grigorieva, I.; Ivanov, Y.; Sablin, S.; Zefirov, N. Antihistamine agent Dimebon as a novel neuroprotector and a cognition enhancer. Ann. N. Y. Acad. Sci., 2001, 939, 425-435.
229. Bachurin, S.O.; Shevtsova, E.P.; Kireeva, E.G.; Oxenkrug, G.F.; Sablin, S.O. Mitochondria as a target for neurotoxins and neuroprotective agents. Ann. N. Y. Acad. Sci., 2003, 993, 334-44; discussion 345-9.
230. Grigorev, V.V.; Dranyi, O.A.; Bachurin, S.O. Comparative study of action mechanisms of dimebon and memantine on AMPA- and NMDA-subtypes glutamate receptors in rat cerebral neurons. Bull. Exp. Biol. Med., 2003, 136, 474-477.
231. Wang, Y.E.; Yue, D.X.; Tang, X.C. Anti-cholinesterase activity of huperzine A. Zhongguo. Yao. Li. Xue. Bao.,1986, 7, 110-113.
232. Ashani, Y.; Peggins, J. O.; Doctor, B.P. Mechanism of inhibition of cholinesterases by huperzine A. Biochem. Biophys. Res. Commun., 1992, 184, 719-726.
233. Saxena, A.; Qian, N.; Kovach, I.M.; Kozikowski, A.P.; Pang, Y.P.; Vellom, D.C.; Radic, Z.; Quinn, D.; Taylor, P.; Doctor, B. P. Identification of amino acid residues involved in the binding of Huperzine A to cholinesterases. Protein Sci., 1994, 3, 1770-1778.
234. Peng, Y.; Lee, D.Y.; Jiang, L.; Ma, Z.; Schachter, S.C.; Lemere, C.A. Huperzine A regulates amyloid precursor protein processing via protein kinase C and mitogen-activated protein kinase pathways in neuroblastoma SK-N-SH cells over-expressing wild type human amyloid precursor protein 695. Neuroscience, 2007, 150, 386-395.
235. Ved, H. S.; Koenig, M. L.; Dave, J. R.; Doctor, B. P. Huperzine A, a potential therapeutic agent for dementia, reduces neuronal cell death caused by glutamate. Neuroreport, 1997, 8, 963-968.
236. Decker, M.; Kraus, B.; Heilmann, J. Design, synthesis and pharmacological evaluation of hybrid molecules out of quinazolinimines and lipoic acid lead to highly potent and selective butyrylcholinesterase inhibitors with antioxidant properties. Bioorg. Med. Chem., 2008, 16, 4252-4261.
237. Kamal, M.A.; Klein, P.; Luo, W.; Li, Y.; Holloway, H.W.; Tweedie, D.; Greig, N.H. Kinetics of human serum butyrylcholinesterase inhibition by a novel experimental Alzheimer therapeutic, dihydrobenzodioxepine cymserine. Neurochem. Res., 2008, 33, 745-753.
238. Raina, P.; Santaguida, P.; Ismaila, A.; Patterson, C.; Cowan, D.; Levine, M.; Booker, L.; Oremus, M. Effectiveness of cholinesterase inhibitors and memantine for treating dementia: evidence review for a clinical practice guideline. Ann. Intern. Med., 2008, 148, 379-397.
239. Fallarero, A.; Oinonen, P.; Gupta, S.; Blom, P.; Galkin, A.; Mohan, C.G.; Vuorela, P.M. Inhibition of acetylcholinesterase by coumarins: the case of coumarin 106. Pharmacol. Res., 2008, 58, 215-221.
240. Huang, L.; Luo, Z.; He, F.; Lu, J.; Li, X. Synthesis and biological evaluation of a new series of berberine derivatives as dual inhibitors of acetylcholinesterase and butyrylcholinesterase. Bioorg. Med. Chem., 2010, 18, 4475-4484.
241. Pavlov, V.A.; Parrish, W.R.; Rosas-Ballina, M.; Ochani, M.; Puerta, M.; Ochani, K.; Chavan, S.; Al-Abed, Y.; Tracey, K.J. Brain acetylcholinesterase activity controls systemic cytokine levels through the cholinergic anti-inflammatory pathway. Brain. Behav. Immun., 2009, 23, 41-45.
242. Terry, A.V.; Buccafusco, J.J. The cholinergic hypothesis of age and Alzheimer's diseaserelated cognitive deficits: recent challenges and their implications for novel drug development. J. Pharmacol. Exp. Ther., 2003, 306, 821-827.
243. Nizri, E.; Adani, R.; Meshulam, H.; Amitai, G.; Brenner, T. Bifunctional compounds eliciting both anti-inflammatory and cholinergic activity as potential drugs for neuroinflammatory impairments. Neurosci. Lett., 2005, 376, 46-50.
244. Laskin, J.D.; Fabio, K.; Lacey, C.J.; Young, S.; Mohanta, P.; Guillon, C.; Heindel, N.D.; Huang, M.T.; Heck, D.E. Unique Dual-Action Therapeutics, U. S. Patent Pending, PCT/US2009/005961, filed November 3, 2009.
245. Young, S.; Fabio, K.; Guillon, C.; Mohanta, P.; Halton, T.A.; Heck, D.E.; Flowers, R.A.; Laskin, J.D.; Heindel, N.D. Peripheral site acetylcholinesterase inhibitors targeting both inflammation and cholinergic dysfunction. Bioorg. Med. Chem. Lett., 2010, 20, 2987-2990.
246. Hardy, J.; Selkoe, D.J. The amyloid hypothesis of Alzheimer's disease: progress and problems on the road to therapeutics. Science, 2002, 297, 353-356.
247. Alvarez, A.; Alarcon, R.; Opazo, C.; Campos, E. O.; Munoz, F.J.; Calderon, F.H.; Dajas, F.; Gentry, M.K.; Doctor, B.P.; De Mello, F.G.; Inestrosa, N.C. Stable complexes involving acetylcholinesterase and amyloid-beta peptide change the biochemical properties of the enzyme and increase the neurotoxicity of Alzheimer's fibrils. J. Neurosci., 1998, 18, 3213-3223.
248. Alvarez, A.; Opazo, C.; Alarcon, R.; Garrido, J.; Inestrosa, N.C. Acetylcholinesterase promotes the aggregation of amyloid-beta-peptide fragments by forming a complex with the growing fibrils. J. Mol. Biol., 1997, 272, 348-361.
249. Munoz-Torrero, D. Acetylcholinesterase inhibitors as disease-modifying therapies for Alzheimer's disease. Curr. Med. Chem., 2008, 15, 2433-2455.
250. Munoz-Muriedas, J.; Lopez, J.M.; Orozco, M.; Luque, F.J. Molecular modelling approaches to the design of acetylcholinesterase inhibitors: new challenges for the treatment of Alzheimer's disease. Curr. Pharm. Des., 2004, 10, 3131-3140.
251. Rizzo, S.; Riviere, C.; Piazzi, L.; Bisi, A.; Gobbi, S.; Bartolini, M.; Andrisano, V.; Morroni, F.; Tarozzi, A.; Monti, J. P.; Rampa, A. Benzofuran-based hybrid compounds for the inhibition of cholinesterase activity, beta amyloid aggregation, and abeta neurotoxicity. J. Med. Chem., 2008, 51, 2883-2886.
252. Fernandez-Bachiller, M.I.; Perez, C.; Campillo, N.E.; Paez, J.A.; Gonzalez-Munoz, G.C.; Usan, P.; Garcia-Palomero, E.; Lopez, M.G.; Villarroya, M.; Garcia, A.G.; Martinez, A.; Rodriguez-Franco, M.I. Tacrine-melatonin hybrids as multifunctional agents for Alzheimer's disease, with cholinergic, antioxidant, and neuroprotective properties. ChemMedChem, 2009, 4, 828-841.
253. Li, Y.P.; Ning, F.X.; Yang, M.B.; Li, Y.C.; Nie, M.H.; Ou, T.M.; Tan, J.H.; Huang, S.L.; Li, D.; Gu, L.Q.; Huang, Z.S. Syntheses and characterization of novel oxoisoaporphine derivatives as dual inhibitors for cholinesterases and amyloid beta aggregation. Eur. J. Med. Chem., 2011, 46, 1572-1581.
254. Belluti, F.; Piazzi, L.; Bisi, A.; Gobbi, S.; Bartolini, M.; Cavalli, A.; Valenti, P.; Rampa, A. Design, synthesis, and evaluation of benzophenone derivatives as novel acetylcholinesterase inhibitors. Eur. J. Med. Chem., 2009, 44, 1341-1348.
255. Bartolini, M.; Bertucci, C.; Cavrini, V.; Andrisano, V. beta-Amyloid aggregation induced by human acetylcholinesterase: inhibition studies. Biochem. Pharmacol., 2003, 65, 407-416.
256. Belluti, F.; Bartolini, M.; Bottegoni, G.; Bisi, A.; Cavalli, A.; Andrisano, V.; Rampa, A. Benzophenone-based derivatives: a novel series of potent and selective dual inhibitors of acetylcholinesterase and acetylcholinesterase-induced beta-amyloid aggregation. Eur. J. Med. Chem., 2011, 46, 1682-1693.
257. Mao, F.; Huang, L.; Luo, Z.; Liu, A.; Lu, C.; Xie, Z.; Li, X. O-Hydroxyl- or o-amino benzylamine-tacrine hybrids: Multifunctional biometals chelators, antioxidants, and inhibitors of cholinesterase activity and amyloid-β aggregation. Bioorg. Med. Chem., 2012, 20, 5884-5892.
258. Hou, J. Q.; Tan, J. H.; Wang, X. X.; Chen, S. B.; Huang, S. Y.; Yan, J. W.; Chen, S. H.; Ou, T. M.; Luo, H. B.; Li, D.; Gu, L. Q.; Huang, Z. S. Impact of planarity of unfused aromatic molecules on G-quadruplex binding: learning from isaindigotone derivatives. Org. Biomol. Chem., 2011, 9, 6422-6436.
259. Lipton, S. A. Paradigm shift in neuroprotection by NMDA receptor blockade: memantine and beyond. Nat. Rev. Drug Discov., 2006, 5, 160-170.
260. González-Muñoz, G. C.; Arce, M. P.; Lopez, B.; Perez, C.; Villarroya, M.; Lopez, M. G.; Garcia, A. G.; Conde, S.; Rodriguez-Franco, M. I. Old phenothiazine and dibenzothiadiazepine derivatives for tomorrow's neuroprotective therapies against neurodegenerative diseases. Eur. J. Med. Chem., 2010, 45, 6152-6158.
261. Zhu, Y.; Xiao, K.; Ma, L.; Xiong, B.; Fu, Y.; Yu, H.; Wang, W.; Wang, X.; Hu, D.; Peng, H.; Li, J.; Gong, Q.; Chai, Q.; Tang, X.; Zhang, H.; Li, J.; Shen, J. Design, synthesis and biological evaluation of novel dual inhibitors of acetylcholinesterase and beta-secretase. Bioorg. Med. Chem., 2009, 17, 1600-1613.
262. Piazzi, L.; Cavalli, A.; Colizzi, F.; Belluti, F.; Bartolini, M. Multi-target-directed coumarin derivatives: hAChE and BACE1 inhibitors as potential anti-Alzheimer compounds. Bioorg. Med. Chem. Lett., 2008, 18, 423-426.
263. Rizzo, S.; Bisi, A.; Bartolini, M.; Mancini, F.; Belluti, F.; Gobbi, S.; Andrisano, V.; Rampa, A. Multi-target strategy to address Alzheimer's disease: Design, synthesis and biological evaluation of new tacrine-based dimers. Eur. J. Med. Chem., 2011, 46, 4336-4343.
264. Rollinger, J.M.; Hornick, A.; Langer, T.; Stuppner, H.; Prast, H. Acetylcholinesterase inhibitory activity of scopolin and scopoletin discovered by virtual screening of natural products. J. Med. Chem., 2004, 47, 6248-6254.
265. Stuppner, H.; Langer, T.; Prast, H.; Rollinger, J.M.; Wolber, G. Use of coumarin derivatives. EP04009431.0. 2005
266. Muschietti, L.; Gorzalczany, S.; Ferraro, G.; Acevedo, C.; Martino, V. Phenolic compounds with anti-inflammatory activity from Eupatorium buniifolium. Planta Med., 2001, 67, 743-744.
267. Calixto, J.B.; Otuki, M.F.; Santos, A.R. Anti-inflammatory compounds of plant origin. Part I. Action on arachidonic acid pathway, nitric oxide and nuclear factor kappa B (NFkappaB). Planta. Med., 2003, 69, 973-983.
268. Kim, N.Y.; Pae, H.O.; Ko, Y.S.; Yoo, J.C.; Choi, B.M.; Jun, C.D.; Chung, H.T.; Inagaki, M.; Higuchi, R.; Kim, Y.C. In vitro inducible nitric oxide synthesis inhibitory active constituents from Fraxinus rhynchophylla. Planta. Med., 1999, 65, 656-658.
269. Kang, T.H.; Pae, H.O.; Jeong, S.J.; Yoo, J.C.; Choi, B.M.; Jun, C.D.; Chung, H.T.; Miyamoto, T.; Higuchi, R.; Kim, Y.C. Scopoletin: an inducible nitric oxide synthesis inhibitory active constituent from Artemisia feddei. Planta. Med., 1999, 65, 400-403.
270. Shaw, C.Y.; Chen, C.H.; Hsu, C.C.; Chen, C.C.; Tsai, Y.C. Antioxidant properties of scopoletin isolated from Sinomonium acutum. Phytother. Res., 2003, 17, 823-825.
271. Toda, S. Inhibitory effects of phenylpropanoid metabolites on copper-induced protein oxidative modification of mice brain homogenate, in vitro. Biol. Trace Elem. Res., 2002, 85, 183-188.
272. Hornick, A.; Lieb, A.; Vo, N.P.; Rollinger, J.M.; Stuppner, H.; Prast, H. The coumarin scopoletin potentiates acetylcholine release from synaptosomes, amplifies hippocampal long-term potentiation and ameliorates anticholinergic- and age-impaired memory. Neuroscience., 2011, 197, 280-292.
273. Carlier, P.R.; Du, D.M.; Han, Y.F.; Liu, J.; Perola, E.; Williams, I.D.; Pang, Y.P. Dimerization of an inactive fragment of Huperzine A produces a drug with twice the potency of the patural product. Angew. Chem. Int. Ed Engl., 2000, 39, 1775-1777.
274. 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.
275. 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.
276. Cui, W.; Li, W.; Zhao, Y.; Mak, S.; Gao, Y.; Luo, J.; Zhang, H.; Liu, Y.; Carlier, P.R.; Rong, J.; Han, Y. Preventing H2O2-induced apoptosis in cerebellar granule neurons by regulating the VEGFR-2/Akt signaling pathway using a novel dimeric antiacetylcholinesterase bis(12)-hupyridone. Brain Res., 2011, 1394, 14-23.
277. Cui, W.; Cui, G.Z.; Li, W.; Zhang, Z.; Hu, S.; Mak, S.; Zhang, H.; Carlier, P.R.; Choi, C.L.; Wong, Y.T.; Lee, S.M.; Han, Y. Bis(12)-hupyridone, a novel multifunctional dimer, promotes neuronal differentiation more potently than its monomeric natural analog huperzine A possibly through alpha7 nAChR. Brain. Res., 2011, 1401, 10-17.
278. Zhao, Y.; Dou, J.; Luo, J.; Li, W.; Chan, H.H.; Cui, W.; Zhang, H.; Han, R.; Carlier, P.R.; Zhang, X.; Han, Y. Neuroprotection against excitotoxic and ischemic insults by bis(12)- hupyridone, a novel anti-acetylcholinesterase dimer, possibly via acting on multiple targets. Brain Res., 2011, 1421, 100-109.