Multi-target therapeutics for neuropsychiatric and neurodegenerative disorders

Drug Discovery Today

Volumn 21, Issue 12, 2016, Pages 1886-1914

  Bawa, Priya ^a   Pradeep, Priyamvada ^a   Kumar, Pradeep ^a   Choonara, Yahya E ^a   Modi, Girish ^a   Pillay, Viness ^a  

^a UNIVERSITY OF THE WITWATERSRAND   (South Africa)

Author keywords

[No Author keywords available]

Indexed keywords

ALZHEIMER DISEASE; ANXIETY DISORDER; BIPOLAR DISORDER; DEGENERATIVE DISEASE; DEPRESSION; DRUG TARGETING; HUMAN; MENTAL DISEASE; MOOD DISORDER; PARKINSON DISEASE; REVIEW; SCHIZOPHRENIA; ANIMAL; DRUG DESIGN;

LIGAND;

ANIMALS; DRUG DESIGN; HUMANS; LIGANDS; MENTAL DISORDERS; NEURODEGENERATIVE DISEASES;

EID: 84994138323     PISSN: 13596446     EISSN: 18785832     Source Type: Journal    
DOI: 10.1016/j.drudis.2016.08.001     Document Type: Review

References (308)

1. 1 Bosch, F., Rosich, L., The contributions of Paul Ehrlich to pharmacology: a tribute on the occasion of the centenary of his Nobel prize. Pharmacology 82 (2008), 171–179.
2. 2 Brodie, J.S., et al. Polypharmacology shakes hands with complex aetiopathology. Trends Pharmacol. Sci. 36 (2015), 802–821.
3. 3 Yoo, C.B., Jones, P.A., Epigenetic therapy of cancer: past, present and future. Nat. Rev. Drug Discov. 2 (2006), 37–50.
4. 4 Lu, J-J., et al. Multi-target drugs: the trend of drug research and development. PLoS One, 7, 2012, e40262.
5. 5 Vitali, F., et al. Network-based target ranking for polypharmacological therapies. J. Biomed. Info. 46 (2013), 876–881.
6. 6 Lavecchia, A., Cerchia, C., In silico methods to address polypharmacology: current status, applications and future perspectives. Drug Discov. Today 21 (2016), 288–298.
7. 7 Zimmermann, G.R., et al. Multi-target therapeutics: when the whole is greater than the sum of the parts. Drug Discov. Today 12 (2007), 34–42.
8. 8 Baylin, S.B., Ohm, J.E., Epigenetic gene silencing in cancer – a mechanism for early oncogenic pathway addiction?. Nat. Rev. Cancer 6 (2006), 107–116.
9. 9 Rawlins, M.D., Cutting the cost of drug development?. Nat. Rev. Drug Discov. 3 (2004), 360–364.
10. 10 Eichler, H.G., et al. Balancing early market access to new drugs with the need for benefit/risk data: a mounting dilemma. Nat. Rev. Drug Discov. 7 (2008), 818–826.
11. 11 Kola, I., The state of innovation in drug development. Clin. Pharmacol. Ther. 83 (2008), 227–230.
12. 12 Capdeville, R., et al. Glivec (STI571, imatinib), a rationally developed, targeted anticancer drug. Nat. Rev. Drug Discov. 1 (2002), 493–502.
13. 13 Kibble, M., et al. Transcriptional response networks for elucidating mechanisms of action of multitargeted agents. Drug Discov. Today 21 (2016), 1063–1075.
14. 14 Wermuth, C.G., Multitargeted drugs: the end of the ‘one-target-one-disease’ philosophy?. Drug Discov. Today 9 (2004), 826–827.
15. 15 Keiser, M.J., et al. Predicting new molecular targets for known drugs. Nature 462 (2009), 175–181.
16. 16 Jordan, V.C., Fourteenth Gaddum Memorial Lecture. A current view of tamoxifen for the treatment and prevention of breast cancer. Br. J. Pharmacol. 110 (1993), 507–517.
17. 17 Armani, F., et al. Tamoxifen use for the management of mania: a review of current preclinical evidence. Psychopharmacol. 231 (2014), 639–649.
18. 18 Blagosklonny, M.V., Matching targets for selective cancer therapy. Drug Discov. Today 8 (2003), 1104–1107.
19. 19 Cuthbert, B.N., Insel, T.R., Toward the future of psychiatric diagnosis: the seven pillars of RDoC. BMC Medicine 11 (2013), 1–8.
20. 20 Mirnezami, R., et al. Preparing for precision medicine. N. Engl. J. Med. 366 (2012), 489–491.
21. 21 Goedert, M., Spillantini, M.G., A century of Alzheimer's disease. Science 314 (2006), 777–781.
22. 22 Silver, L.L., Multi-targeting by monotherapeutic antibacterials. Nat. Rev. Drug Discov. 6 (2007), 41–55.
23. 23 Youdim, M.B., et al. Why should we use multifunctional neuroprotective and neurorestorative drugs for Parkinson's disease?. Parkinsonism Relat. Disord. 13 (2007), 281–291.
24. 24 Cavalli, A., et al. Multi-target-directed ligands to combat neurodegenerative diseases. J. Med. Chem. 51 (2008), 347–372.
25. 25 Petrelli, A., Giordano, S., From single- to multi-target drugs in cancer therapy: when aspecificity becomes an advantage. Curr. Med. Chem. 15 (2008), 422–432.
26. 26 Millan, M.J., Dual and triple-acting agents for treating core and co-morbid symptoms of major depression: novel concepts, new drugs. Neurotherapeutics 6 (2009), 53–77.
27. 27 Bottegoni, G., et al. The role of fragment-based and computational methods in polypharmacology. Drug Discov. Today 17 (2012), 23–34.
28. 28 Calvano, S.E., et al. A network-based analysis of systemic inflammation in humans. Nature 437 (2005), 1032–1037.
29. 29 Zhong, W., Wang, Y., Modular pharmacology: deciphering the interacting structural organization of the targeted networks. Drug Discov. Today 18 (2013), 561–566.
30. 30 National Institute of Mental Health, The National Institute of Mental Health Strategic Plan. 2008 Available at: http://www.nimh.nih.gov/about/strategic-planning-reports/index.shtml.
31. 31 Korcsmáros, T., et al. How to design multi-target drugs: target search options in cellular networks. Exp. Opin. Drug Discov. 2 (2007), 1–10.
32. 32 Bansal, Y., Silakari, O., Multifunctional compounds: smart molecules for multifactorial diseases. Eur. J. Med. Chem. 76 (2014), 31–42.
33. 33 Morphy, R., et al. From magic bullets to designed multiple ligands. Drug Discov. Today 9 (2004), 641–651.
34. 34 Morphy, R., Rankovic, Z., Designed multiple ligands. An emerging drug discovery paradigm. J. Med. Chem. 48 (2005), 6523–6543.
35. 35 Rocha, D.N., et al. High-throughput platforms for the screening of new therapeutic targets for neurodegenerative diseases. Drug Discov. Today, 2016, 10.1016/j.drudis.2016.05.005.
36. 36 Xu, X.H., Zhong, Z., Disease modeling and drug screening for neurological diseases using human induced pluripotent stem cells. Acta Pharmacol. Sin. 34 (2013), 755–764.
37. 37 Millan, M.J., On ‘polypharmacy’ and multi-target agents, complementary strategies for improving the treatment of depression: a comparative appraisal. Int. J. Neuropsychoph. 17 (2014), 1009–1037.
38. 38 Millan, M.J., Multi-target strategies for the improved treatment of depressive states: conceptual foundations and neuronal substrates, drug discovery and therapeutic application. Pharmacol. Ther. 110 (2006), 135–370.
39. 39 Roth, B.L., et al. Magic shotguns versus magic bullets: selectively non-selective drugs for mood disorders and schizophrenia. Nat. Rev. Drug Discov. 3 (2004), 353–359.
40. 40 Penrod, N.M., et al. Systems genetics for drug target discovery. Trends Pharmacol. Sci. 32 (2011), 623–630.
41. 41 Sanchez-Mut, J.V., et al. Aberrant epigenetic landscape in intellectual disability. Prog. Brain Res. 197 (2012), 53–71.
42. 42 Sun, H., et al. Epigenetics of the depressed brain: role of histone acetylation and methylation. Neuropsychopharmacology 38 (2012), 124–137.
43. 43 Uher, R., Genes, environment, and individual differences in responding to treatment for depression. Harv. Rev. Psychiatry 19 (2011), 109–124.
44. 44 Mouillet-Richard, S., et al. MicroRNAs and depression. Neurobiol. Dis. 46 (2012), 272–278.
45. 45 Millan, M.J., An epigenetic framework for neurodevelopmental disorders: from pathogenesis to therapy. Neuropharmacology 68 (2013), 2–82.
46. 46 Whiting, P.J., GABA-A receptors: a viable target for novel anxiolytics?. Curr. Opin. Pharmacol. 6 (2006), 24–29.
47. 47 Sinclair, L.I., Nutt, D.J., Neurobiology of psychiatric disorders: anxiolytics. Aminof, M.J., (eds.) Handbook of Clinical Neurology, vol. 106, 2012, Elsevier, 669–679.
48. 48 Wu, E.Q., et al. The economic burden of schizophrenia in the United States in 2002. J. Clin. Psychiatry 66 (2005), 1122–1129.
49. 49 Sanchez-Moreno, J., et al. Functioning and disability in bipolar disorder: an extensive review. Psychother. Psychosom. 78 (2009), 285–297.
50. 50 Conus, P., et al. Public health significance of bipolar disorder: implications for early intervention and prevention. Bipolar Disord. 16 (2014), 548–556.
51. 51 Kim, D.H., et al. Building a better antipsychotic: receptor targets for the treatment of multiple symptom dimensions of schizophrenia. Neurotherapeutics 6 (2009), 78–85.
52. 52 Stahl, S.M., Multifunctional drugs: a novel concept for psychopharmacology. CNS Spectr. 1 (2009), 71–73.
53. 53 Bleuler, E., Dementia Praecox or the Group of Schizophrenias. 1950, International University Press.
54. 54 Kraepelin, E., (eds.) Clinical Psychiatry, 1913, William Wood Company, New York.
55. 55 Lake, C.R., Hurwitz, N., Schizoaffective disorders are psychotic mood disorders; there are no schizoaffective disorders. Psychiatry Res. 143 (2006), 255–287.
56. 56 Schneider, K., (eds.) Clinical Psychopathology, 1959, Grune & Stratton, Inc., New York.
57. 57 American Psychiatric Association, Diagnostic and Statistical Manual (DSM) 5. Schizophrenia. 2013, American Psychiatric Association.
58. 58 Townsend, M.H., Wilson, M.S., Comorbid anxiety disorders and divalproex sodium use among partial hospital patients with psychotic disorders. Compr. Psychiatry 46 (2005), 368–370.
59. 59 Wong, E.H.F., et al. The effectiveness of multi-target agents in schizophrenia and mood disorders: relevance of receptor signature to clinical action. Pharmacol. Ther. 126 (2010), 173–185.
60. 60 Newcomer, J.W., Comparing the safety and efficacy of atypical antipsychotics in psychiatric patients with comorbid medical illnesses. J. Clin. Psychiatry 70 (2009), 30–36.
61. 61 Bantick, R.A., et al. The 5-HT1A receptor in schizophrenia: a promising target for novel atypical neuroleptics?. J. Psychopharmacol. 15 (2001), 37–46.
62. 62 Di Matteo, V., et al. Role of serotonin (2C) receptors in the control of brain dopaminergic function. Pharmacol. Biochem. Behav. 71 (2002), 727–734.
63. 63 Dean, B., et al. Muscarinic receptors in schizophrenia. Curr. Mol. Med. 3 (2003), 419–426.
64. 64 Arnsten, A.F., Adrenergic targets for the treatment of cognitive deficits in schizophrenia. Psychopharmacology 174 (2004), 25–31.
65. 65 Abbas, A.I., et al. Amisulpride is a potent 5-HT7 antagonist: relevance for antidepressant in vivo. Psychopharmacology 205 (2009), 119–128.
66. 66 Moghaddam, B., Bringing order to the glutamate chaos in schizophrenia. Neuron 40 (2003), 881–884.
67. 67 Martin, L.F., et al. Alpha-7 nicotinic receptor agonists: potential new candidates for the treatment of schizophrenia. Psychopharmacology 174 (2004), 54–64.
68. 68 Marek, G., Merchant, K., Developing therapeutics for schizophrenia and other psychotic disorders. NeuroRx 2 (2005), 579–589.
69. 69 Gray, J.A., Roth, B.L., The pipeline and future of drug development in schizophrenia. Mol. Psychiatry 12 (2007), 904–922.
70. 70 Bishara, D., Taylor, D., Upcoming agents for the treatment of schizophrenia: mechanism of action, efficacy and tolerability. Drugs 68 (2008), 2269–2292.
71. 71 Freedman, R., et al. Initial phase 2 trial of a nicotinic agonist in schizophrenia. Am. J. Psychiatry 165 (2008), 1040–1047.
72. 72 Sodhi, M., et al. Role of glutamate in schizophrenia: integrating excitatory avenues of research. Expert Rev. Neurother. 8 (2008), 1389–1406.
73. 73 Seeman, P., Atypical antipsychotics: mechanism of action. Can. J. Psychiatry 47 (2002), 27–38.
74. 74 Butini, S., et al. Discovery of a new class of potential multifunctional atypical antipsychotic agents targeting dopamine D3 and serotonin 5-HT1A and 5-HT2A receptors: design, synthesis, and effects on behavior. J. Med. Chem. 52 (2009), 151–169.
75. 75 Zajdel, P., et al. Antidepressant and antipsychotic activity of new quinoline- and isoquinoline-sulfonamide analogs of aripiprazole targeting serotonin 5-HT1A/5-HT2A/5-HT7 and dopamine D2/D3 receptors. Eur. J. Med. Chem. 60 (2013), 42–50.
76. 76 Zajdel, P., et al. Quinoline- and isoquinoline-sulfonamide derivatives of LCAP as potent CNS multi-receptor – 5-HT1A/5-HT2A/5-HT7 and D2/D3/D4 – agents: the synthesis and pharmacological evaluation. Bioorg. Med. Chem. 20 (2012), 1545–1556.
77. 77 Bhosale, S.H., et al. Design, synthesis, pharmacological evaluation and computational studies of 1-(biphenyl-4-yl)-2-[4-(substituted phenyl)-piperazin-1-yl]ethanones as potential antipsychotics. Eur. J. Med. Chem. 74 (2014), 358–365.
78. 78 Li, P., et al. Discovery of a tetracyclic quinoxaline derivative as a potent and orally active multifunctional drug candidate for the treatment of neuropsychiatric and neurological disorders. J. Med. Chem. 57 (2014), 2670–2682.
79. 79 Oswald, P., et al. Current issues in bipolar disorder: a critical review. Eur. Neuropsychopharmacol. 17 (2007), 687–695.
80. 80 Angst, J., Bipolar disorders in DSM-5: strengths, problems and perspectives. Int. J. Bipolar Dis. 1 (2013), 1–3.
81. 81 Fountoulakis, K.N., et al. Efficacy of pharmacotherapy in bipolar disorder: a report by the WPA section on pharmacopsychiatry. Eur. Arch. Psychiatry Clin. Neurosci. 262 (2012), 1–48.
82. 82 de Bartolomeis, A., et al. Intracellular pathways of antipsychotic combined therapies: implication for psychiatric disorders treatment. Eur. J. Pharmacol. 718 (2013), 502–523.
83. 83 Grunze, H., et al. The World Federation of Societies of Biol. Psychiatry (WFSBP) guidelines for the biological treatment of bipolar disorders: update 2012 on the long-term treatment of bipolar disorder. World J. Biol. Psychiatry 14 (2013), 154–219.
84. 84 Sachs, G.S., et al. The pharmacologic treatment of bipolar disorder. J. Clin. Psychiatry 72 (2011), 704–715.
85. 85 Licht, R.W., Lithium: still a major option in the management of bipolar disorder. CNS Neurosci. Ther. 18 (2012), 219–226.
86. 86 Bourin, M., Thibaut, F., How assess drugs in the treatment of acute bipolar mania?. Front. Pharmacol. 4 (2013), 1–11.
87. 87 Buoli, M., et al. Is the combination of a mood stabilizer plus an antipsychotic more effective than mono-therapies in long-term treatment of bipolar disorder? A systematic review. J. Affect. Disord. 152–154 (2014), 12–18.
88. 88 Ágai-Csongor, E., et al. Discovery of cariprazine (RGH-188): a novel antipsychotic acting on dopamine D3/D2 receptors. Bioorg. Med. Chem. Lett. 22 (2012), 3437–3440.
89. 89 Durgam, S., et al. The efficacy and tolerability of cariprazine in acute mania associated with bipolar I disorder: a phase II trial. Bipolar Disord. 17 (2015), 63–75.
90. 90 Kiss, B., et al. Cariprazine (RGH-188), a dopamine D(3) receptor-preferring, D(3)/D(2) dopamine receptor antagonist-partial agonist antipsychotic candidate: in vitro and neurochemical profile. J. Pharm. Exp. Ther. 333 (2010), 328–340.
91. 91 Cho, D.I., et al. Current perspectives on the selective regulation of dopamine D(2) and D(3) receptors. Arch. Pharm. Res. 33 (2010), 1521–1538.
92. 92 Gross, G., Drescher, K., The role of dopamine D(3) receptors in antipsychotic activity and cognitive functions. Handb. Exp. Pharmacol. 213 (2012), 167–210.
93. 93 Leggio, G.M., et al. Dopamine D3 receptor as a new pharmacological target for the treatment of depression. Eur. J. Pharmacol. 719 (2013), 25–33.
94. 94 Sachs, G.S., et al. Cariprazine in the treatment of acute mania in bipolar I disorder: a double-blind, placebo-controlled, Phase III trial. J. Affect. Disord. 174 (2015), 296–302.
95. 95 Jackson, A., et al. A systematic review of manic and depressive prodromes. J. Affect. Disord. 74 (2003), 209–217.
96. 96 McClung, C.A., Circadian genes, rhythms, and the biology of mood disorders. Pharmacol. Ther. 114 (2007), 222–232.
97. 97 Harvey, A.G., Sleep and circadian rhythms in bipolar disorder: seeking synchrony, harmony and regulation. Am. J. Psychiatry 165 (2008), 820–829.
98. 98 Calabrese, J.R., et al. Agomelatine adjunctive therapy for acute bipolar depression: preliminary open data. Bipolar Disord. 9 (2007), 628–635.
99. 99 DiazGranados, N., Zarate, C.A. Jr., A review of the preclinical and clinical evidence for protein kinase C as a target for drug development for bipolar disorder. Curr. Psychiatry Rep. 10 (2008), 510–519.
100. 100 Kent, J.M., et al. Molecular targets in the treatment of anxiety. Biol. Psychiatry 52 (2002), 1008–1030.
101. 101 Griebel, G., Holmes, A., 50 years of hurdles and hope in anxiolytic drug discovery. Nat. Rev. Drug Discov. 12 (2013), 667–687.
102. 102 Holmes, A., et al. Neuropeptide systems as novel therapeutic targets for depression and anxiety disorders. Trends Pharmacol. Sci. 24 (2003), 580–588.
103. 103 Steckler, T., et al. Developing novel anxiolytics: improving preclinical detections and clinical assessment, animal and translational models for CNS drug discovery. McArthur, R., Borsini, F., (eds.) Psychiatric Disorders, vol. 1, 2008, Academic Press, 117–132.
104. 104 Louvet, S., et al. The current role of long-term benzodiazepines for the treatment of generalized anxiety. Ost. Fam. Phys. 1 (2015), 19–25.
105. 105 Salzman, C., Shader, R., Not again: benzodiazepines once more under attack. J. Clin. Psychopharm. 35 (2015), 493–495.
106. 106 Perna, G., et al. Long-term pharmacological treatments of anxiety disorders: an updated systematic review. Curr. Psych. Rep., 18, 2016, 23.
107. A receptor subtypes. Nat. Rev. Drug Discov. 10 (2011), 685–697.
108. 108 Borwin, B., et al. Efficacy of treatments for anxiety disorders: a meta-analysis. Int. Clin. Psychopharm. 30 (2015), 183–192.
109. 109 Kent, J.M., et al. Efficacy and safety of an adjunctive mGlu2 receptor positive allosteric modulator to a SSRI/SNRI in anxious depression. Prog. Neuropsychopharmacol. Biol. Psychiatry 67 (2016), 66–73.
110. 110 Nutt, D.J., Overview of diagnosis and drug treatments of anxiety disorders. CNS Spectr. 10 (2005), 49–56.
111. 111 Belzung, C., et al. Neuropeptides in psychiatric diseases: an overview with a particular focus on depression and anxiety disorders. CNS Neurol. Disord. Drug Targets 5 (2006), 135–145.
112. 112 van den Pol, A.N., Neuropeptide transmission in brain circuits. Neuron 76 (2012), 98–115.
113. 113 Smith, J.A., et al. Hydration and beyond: neuropeptides as mediators of hydromineral balance, anxiety and stress-responsiveness. Front. Syst. Neurosci. 9 (2015), 1–15.
114. 114 Steckler, T., Developing small molecule nonpeptidergic drugs for the treatment of anxiety disorders: is the challenge still ahead?. Curr. Top. Behav. Neurosci. 2 (2010), 415–428.
115. 115 Griebel, G., Holsboer, F., Neuropeptide receptor ligands as drugs for psychiatric diseases: the end of the beginning?. Nat. Rev. Drug Discov. 11 (2012), 462–478.
116. 116 Krystal, J.H., Potential psychiatric applications of metabotropic glutamate receptor agonists and antagonists. CNS Drugs 24 (2010), 669–693.
117. 117 Stewart, A.M., Kalueff, A.V., Anxiolytic drug discovery: what are the novel approaches and how can we improve them?. Expert Opin. Drug Discov. 9 (2014), 15–26.
118. 118 Rey, A.A., et al. Biphasic effects of cannabinoids in anxiety responses: CB1 and GABA B receptors in the balance of GABAergic and glutamatergic neurotransmission. Neuropsychopharmacology 37 (2012), 2624–2634.
119. 119 Metna-Laurent, M., et al. Bimodal control of fearcoping strategies by CB1 cannabinoid receptors. J. Neurosci. 32 (2012), 7109–7118.
120. 120 Wittchen, H.U., Hoyer, J., Generalized anxiety disorder: nature and course. J. Clin. Psychiatry 62 (2001), 15–21.
121. 121 van Den Berg, S.J., Comparing SSRIs: from chemistry to clinical choice. Hum. Psychopharmacol. 10 (1995), S199–S209.
122. 122 Heinrich, T., et al. Synthesis and structure–activity relationship in a class of indolebutylpiperazines as dual 5-HT(1A) receptor agonists and serotonin reuptake inhibitors. J. Med. Chem. 47 (2004), 4684–4692.
123. 123 Emilien, G., et al. (eds.) Anxiety Disorders: Pathophysiology and Pharmacological Treatment, 2002, Birkhauser.
124. 124 Vardanyan, R., Hruby, V., (eds.) Anxiolytics (tranquillizers) Synthesis of Essential Drugs, 2006, Elsevier, 69–82.
125. 125 Owen, D.R., et al. Stratified medicine in psychiatry: a worrying example or new opportunity in the treatment of anxiety?. J. Psychopharmacol. 27 (2013), 119–122.
126. 126 Duman, R.S., et al. Neural plasticity to stress and antidepressant treatment. Biol. Psychiatry 46 (1999), 1181–1191.
127. 127 Popoli, M., et al. Modulation of synaptic plasticity by stress and antidepressants. Bipolar Disord. 3 (2002), 1–17.
128. 128 Manji, H.K., et al. Enhancing neuronal plasticity and cellular resilience to develop novel, improved therapeutics for difficult-to-treat depression. Biol. Psychiatry 53 (2003), 707–742.
129. 129 Xu, H., et al. Dose-related effects of chronic antidepressants on neuroprotective proteins BDNF, Bcl-2 and Cu/Zn-SOD in rat hippocampus. Neuropsychopharmacology 28 (2003), 53–62.
130. 130 Wong, M.L., Licinio, J., From monoamines to genomic targets: a paradigm shift for drug discovery in depression. Nature 3 (2004), 136–151.
131. 131 Adell, A., et al. Strategies for producing faster acting antidepressants. Drug Discov. Today 10 (2005), 578–585.
132. 132 Davies, M.N., et al. Generalised anxiety disorder – a twin study of genetic architecture, genome-wide association and differential gene expression. PLoS One 10 (2015), 1–15.
133. 133 Wittchen, H.U., et al. Why do people with anxiety disorders become depressed? A prospective-longitudinal community study. Acta Psychiat. Scand. 102 (2000), 14–23.
134. 134 Stein, M.B., et al. Social anxiety disorder and the risk of depression. A prospective community study of adolescents and young adults. Archives Gen. Psychiatry 58 (2001), 251–256.
135. 135 Hunt, C.J., The current status of the diagnostic validity and treatment of generalized anxiety disorder. Curr. Opin. Psychiatry 15 (2002), 157–162.
136. 136 Shorter, E., Tyrer, P., Separation of anxiety and depressive disorders: blind alley in psychopharmacology and classification of disease. BMJ 327 (2003), 158–160.
137. 137 Stein, M.B., Heimberg, R.G., Well-being and life satisfaction in generalized anxiety disorder: comparison to major depressive disorder in a community sample. J. Affect. Disord. 79 (2004), 161–166.
138. 138 Wilhelm, K., et al. The relationship between interpersonal sensitivity, anxiety disorders and major depression. J. Affect. Disord. 79 (2004), 33–41.
139. 139 Zimmerman, M., et al. Which factors influence psychiatrists’ selection of antidepressants?. Am. J. Psychiatry 161 (2004), 1285–1289.
140. 140 Tamminga, C.A., et al. Developing novel treatments for mood disorders: accelerating discovery. Biol. Psychiatry 52 (2002), 589–609.
141. 141 Bajaj, P., Tyrer, P., Managing mood disorders and co-morbid personality disorders. Curr. Opin. Psychiatry 18 (2005), 27–31.
142. 142 Rao, S., Zisook, S., Anxious depression: clinical features and treatment. Curr. Psychiatry Rep. 11 (2009), 429–436.
143. 143 Wiethoff, K., et al. Prevalence and treatment outcome in anxious versus nonanxious depression: results from the German Algorithm Project. J. Clin. Psychiatry 71 (2010), 1047–1054.
144. 144 American Psychiatric Association, Practice guideline for the treatment of patients with major depressive disorder. Am. J. Psychiatry 157:4 Suppl. (2000), 1–45.
145. 145 Thase, M.E., et al. Efficacy of vilazodone on anxiety symptoms in patients with major depressive disorder. J. Clin. Psychopharmacol. 29 (2014), 351–356.
146. 146 Nelson, J.C., Augmentation strategies in depression 2000. J. Clin. Psychiatry 61 (2000), 13–19.
147. 147 Fleurence, R., et al. A systematic review of augmentation strategies for patients with major depressive disorder. Psychopharmacol. Bull. 42 (2009), 57–90.
148. 148 Albert, P.R., Francois, B.L., Modifying 5-HT1A receptor gene expression as a new target for antidepressant therapy. Front. Hum. Neurosci. 4 (2010), 1–7.
149. 149 Volkow, N.D., et al. The slow and longlasting blockade of dopamine transporters in human brain induced by the new antidepressant drug radafaxine predict poor reinforcing effects. Biol. Psychiatry 57 (2005), 640–646.
150. 150 Walther, D.J., et al. Synthesis of serotonin by a second tryptophan hydroxylase isoform. Science, 299, 2003, 76.
151. 151 Wischhof, L., Koch, M., 5-HT2A and mGlu2/3 receptor interactions: on their relevance to cognitive function and psychosis. Behav. Pharmacol. 27 (2016), 1–11.
152. 152 Jenkins, T.A., et al. Influence of tryptophan and serotonin on mood and cognition with a possible role of the gut–brain axis. Nutrition 8 (2016), 1–15.
153. 153 Hornung, J.P., The human raphe nuclei and the serotonergic system. J. Chem. Neuroanat. 26 (2003), 331–343.
154. 154 Gordon, J.A., Hen, R., The serotonergic system and anxiety. Neuromol. Med. 5 (2004), 27–40.
155. 155 Lanfumey, L., et al. Corticosteroid–serotonin interactions in the neurobiological mechanisms of stress-related disorders. Neurosci. Biobehav. Rev. 32 (2008), 1174–1184.
156. 156 Savitz, J., et al. 5-HT(1A) receptor function in major depressive disorder. Prog. Neurobiol. 88 (2009), 17–31.
157. 157 Palacios, J.M., Serotonin receptors in brain revisited. Brain Res., 2015, 10.1016/j.brainres.2015.12.042.
158. 158 Artigas, F., Future directions for serotonin and antidepressants. ACS Chem. Neurosci. 4 (2013), 5–8.
159. 159 Chilmonczyk, Z., et al. Functional selectivity and antidepressant activity of serotonin 1A receptor ligands. Int. J. Mol. Sci. 16 (2015), 18474–18506.
160. 160 Machado-Vieira, R., et al. New targets for rapid antidepressant action. Prog. Neurobiol., 2015, 10.1016/j.pneurobio.2015.12.001.
161. 161 Riad, M., et al. Acute treatment with the antidepressant fluoxetine internalises 5-HT1A autoreceptors and reduces the in vivo binding of the PET radioligand [18F] MPPF in the nucleus raphe dorsalis of rat. J. Neurosci. 24 (2004), 5420–5426.
162. 162 Albert, P.R., Le François, B., Modifying 5-HT1A receptor gene expression as a new target for antidepressant therapy. Front. Neurosci. 4 (2010), 1–7.
163. 163 Millan, M.J., et al. Reciprocal autoreceptor and heteroreceptor control of serotonergic, dopaminergic and noradrenergic transmission in the frontal cortex: relevance to the actions of antidepressant agents. J. Psychopharmacol. 14 (2000), 114–138.
164. 164 Bymaster, F.P., et al. New approaches to developing antidepressants by enhancing monoaminergic neurotransmission. Expert Opin. Investig. Drugs 12 (2003), 531–543.
165. 165 Celada, P., et al. The therapeutic role of 5-HT1A and 5-HT2A receptors in depression. J. Psychiatry Neurosci. 29 (2004), 252–265.
166. 166 Dawson, L.A., Bromidge, S.M., 5-HT1 receptor augmentation strategies as enhanced efficacy: therapeutics for psychiatric disorders. Curr. Top. Med. Chem. 8 (2008), 1008–1023.
167. 167 Romero, L., et al. Modulation of serotonergic function in rat brain by VN2222, a serotonin reuptake inhibitor and 5-HT1A receptor agonist. Neuropsychopharmacology 28 (2003), 445–456.
168. 168 Takeuchi, K., et al. Advances toward new antidepressants beyond SSRIs: 1-aryloxy-3-piperidinylpropan-2-ols with dual 5-HT1A receptor antagonism/SSRI activities. Part 1. Bioorg. Med. Chem. Lett. 13 (2003), 1903–1905.
169. 169 Takeuchi, K., et al. Advances toward new antidepressants beyond SSRIs: 1-aryloxy-3-piperidinylpropan-2-ols with dual 5-HT1A receptor antagonism/SSRI activities. Part 2. Bioorg. Med. Chem. Lett. 13 (2003), 2393–2397.
170. 170 Takeuchi, K., et al. Advances toward new antidepressants beyond SSRIs: 1-aryloxy-3-piperidinylpropan-2-ols with dual 5-HT1A receptor antagonism/SSRI activities. Part 3. Bioorg. Med. Chem. Lett. 13 (2003), 3939–3942.
171. 171 Rocco, V.P., et al. Advances toward new antidepressants beyond SSRIs: 1-aryloxy-3-piperidinylpropan-2-ols with dual 5-HT1A receptor antagonism/SSRI activities. Part 4. Bioorg. Med. Chem. Lett. 14 (2004), 2653–2656.
172. 172 Takeuchi, K., et al. Advances toward new antidepressants beyond SSRIs: 1-aryloxy-3-piperidinylpropan-2-ols with dual 5-HT1A receptor antagonism/SSRI activities. Part 5. Bioorg. Med. Chem. Lett. 16 (2006), 2347–2351.
173. 173 Hughes, Z.A., et al. Simultaneous blockade of 5-HT1A/B receptors and 5-HT transporters results in acute increases in extracellular 5-HT in both rats and guinea pigs: in vivo characterization of the novel 5-HT1A/B receptor antagonist/5-HT transport inhibitor SB-649915-B. Psychopharmacology 192 (2007), 121–133.
174. 174 Starr, K.R., et al. SB-649915-B, a novel 5-HT1A/B autoreceptor antagonist and serotonin reuptake inhibitor, is anxiolytic and displays fast onset activity in the rat social interaction test. Neuropsychopharmacology 32 (2007), 2163–2172.
175. 175 Watson, J.M., Dawson, L.A., Characterization of the potent 5-HT1A/B receptor antagonist and serotonin reuptake inhibitor SB-649915: preclinical evidence for hastened onset of antidepressant/anxiolytic efficacy. CNS Drug Rev. 13 (2007), 206–223.
176. 176 Hatanaka, K., et al. Biochemical profile of YM992, a novel selective serotonin reuptake inhibitor with 5-HT2A receptor antagonistic activity. Neuropharmacol. 35 (1996), 1621–1626.
177. 177 Rotzinger, S., Baker, G.B., Human CYP3A4 and the metabolism of nefazodone and hydroxynefazodone by human liver microsomes and heterologously expressed enzymes. Eur. Neuropsychopharmacol. 12 (2002), 91–100.
178. 178 Leiser, S.C., et al. Serotonergic regulation of prefrontal cortical circuitries involved in cognitive processing: a review of individual 5-HT receptor mechanisms and concerted effects of 5-HT receptors exemplified by the multimodal antidepressant vortioxetine. ACS Chem. Neurosci. 6 (2015), 970–986.
179. 2A receptors in the rat medial prefrontal cortex: an iontophoretic study. Synapse 17 (1994), 173–181.
180. 180 Horst, W.H., Preskorn, S.H., Mechanisms of action and clinical characteristics of three atypical antidepressants: venlafaxine, nefazodone, bupropion. J. Affect. Disord. 51 (1998), 237–254.
181. 181 Bang-Andersen, B., et al. Discovery of 1-[2-(2,4-dimethylphenylsulfanyl)phenyl]piperazine (Lu AA21004): a novel multimodal compound for the treatment of major depressive disorder. J. Med. Chem. 54 (2011), 3206–3221.
182. 182 Westrich, L., et al. In vitro and in vivo effects of the multimodal antidepressant vortioxetine (Lu AA21004) at human and rat targets. Int. J. Psychiatry Clin. Pract., 5, 2012, 47.
183. 183 Celada, P., et al. Serotonin 5-HT1A receptors as targets for agents to treat psychiatric disorders: rationale and current status of research. CNS Drugs 27 (2013), 703–716.
184. 184 Bartoszyk, G.D., et al. EMD 68843, a serotonin reuptake inhibitor with selective presynaptic 5-HT1A receptor agonistic properties. Eur. J. Pharmacol. 322 (1997), 147–153.
185. 185 Khan, A., et al. A randomized, double-blind, placebo-controlled, 8-week study of vilazodone, a serotonergic agent for the treatment of major depressive disorder. J. Clin. Psychiatry 72 (2011), 441–447.
186. 186 Laughren, T.P., et al. Vilazodone: clinical basis for the US Food and Drug Administration's approval of a new antidepressant. J. Clin. Psychiatry 72 (2011), 1166–1173.
187. 187 Reed, C.R., et al. The efficacy profile of vilazodone, a novel antidepressant for the treatment of major depressive disorder. Curr. Med. Res. Opin. 28 (2012), 27–39.
188. 188 Gobert, A., et al. Buspirone modulates basal and fluoxetine-stimulated dialysate levels of dopamine, noradrenaline and serotonin in the frontal cortex of freely moving rats: activation of serotonin1A receptors and blockade of α2-adrenergic receptors underlie its actions. Neuroscience 93 (1999), 1251–1262.
189. 189 Tottori, K., et al. Antidepressant-like responses to the combined sigma and 5-HT1A receptor agonist OPC-14523. Neuropharmacology 41 (2001), 976–988.
190. 190 Jordan, S., et al. In vitro profile of the antidepressant candidate OPC-14523 at rat and human 5-HT1A receptors. Eur. J. Pharmacol. 517 (2005), 165–173.
191. 191 Kaufman, J., et al. The 5-HT1A receptor in major depressive disorder. Eur. Neuropsychopharm. 26 (2016), 397–410.
192. 192 Blier, P.J., Possible neurobiological mechanisms underlying faster onset of antidepressant action. J. Clin. Psychiatry 62 (2001), 12–17.
193. 2A-Adrenoreceptors enhance the serotonergic effects of fluoxetine. Eur. J. Pharmacol. 539 (2006), 164–167.
194. 194 Serres, F., et al. Molecular adaptation to chronic antidepressant treatment: evidence for a more rapid response to the novel α2-adrenoceptor antagonist/5-HT-noradrenaline reuptake inhibitor (SNRI), S35966, compared to the SNRI, venlafaxine. Int. J. Neuropsychopharm. 15 (2012), 617–629.
195. 195 Andrés, J.I., et al. Tricyclic isoxazolines: identification of R226161 as a new antidepressant that combines potent serotonin reuptake inhibition and α2-adrenoceptor antagonism. Bioorg. Med. Chem. 15 (2007), 3649–3660.
196. 196 Gobert, A., et al. The novel antidepressant, S35966, is a mixed serotonin and noradrenaline reuptake inhibitor and an antagonist at α2-adrenoceptors. Eur. Neuropsychopharmacol., 12, 2002, S248.
197. 197 Dekeyne, A., et al. S32212, a novel serotonin type 2C receptor inverse agonist/α2-adrenoceptor antagonist and potential antidepressant: II. A behavioral, neurochemical, and electrophysiological characterization. J. Pharm. Exp. Ther. 340 (2012), 765–780.
198. 198 Passani, M.B., et al. The histamine H3 receptor as a novel therapeutic target for cognitive and sleep disorders. Trends Pharmacol. Sci. 25 (2004), 618–625.
199. 199 Medhurst, A.D., et al. GSK189254, a novel H3 receptor antagonist that binds to histamine H3 receptors in Alzheimer's disease brain and improves cognitive performance in preclinical models. J. Pharm. Exp. Ther. 321 (2007), 1032–1045.
200. 200 Barbier, A.J., et al. Pharmacological characterization of JNJ-28583867, a histamine H3 receptor antagonist and serotonin reuptake inhibitor. Eur. J. Pharmacol. 576 (2007), 43–54.
201. 201 Keith, J.M., et al. Pyrrolidino-tetrahydroisoquinolines bearing pendant heterocycles as potent dual H3 antagonist and serotonin transporter inhibitors. Bioorg. Med. Chem. Lett. 17 (2007), 4374–4377.
202. 202 Abe, Y., et al. Pharmacological characterization of RS-1259, an orally active dual inhibitor of acetylcholinesterase and serotonin transporter, in rodents: possible treatment of Alzheimer's disease. J. Pharmacol. Sci. 93 (2003), 95–105.
203. 203 Toda, N., et al. Design, synthesis and structure-activity relationships of dual inhibitors of acetylcholinesterase and serotonin transporter as potential agents for Alzheimer's disease. Bioorg. Med. Chem. 11 (2003), 1935–1955.
204. 204 McKenna, M.T., et al. Novel tacrine analogues for potential use against Alzheimer's disease: potent and selective acetylcholinesterase inhibitors and 5-HT uptake inhibitors. J. Med. Chem. 40 (1997), 3516–3523.
205. 205 Van der Schyf, C.J., et al. Multifunctional drugs with different CNS targets for neuropsychiatric disorders. J. Neurochem. 99 (2006), 1033–1048.
206. 206 Möhler, H., The GABA system in anxiety and depression and its therapeutic potential. Neuropharmacology 62 (2012), 42–53.
207. B receptor as a target for antidepressant drug action. Br. J. Pharmacol. 162 (2010), 1–17.
208. 208 Paul, I.A., Skolnick, P., Glutamate and depression: clinical and preclinical studies. Ann. N. Y. Acad. Sci. 1003 (2003), 250–272.
209. 209 Sanacora, G., et al. Clinical studies implementing glutamate neurotransmission in mood disorders. Ann. N. Y. Acad. Sci. 1003 (2003), 292–308.
210. 210 Black, M.D., Therapeutic potential of positive AMPA modulators and their relationship to AMPA receptor subunits: a review of preclinical data. Psychopharmacology 179 (2005), 154–163.
211. 211 Millan, M.J., N-methyl-D-aspartate receptors as a target for improved antipsychotic agents: novel insights and clinical perspectives. Psychopharmacology 179 (2005), 30–53.
212. 212 Linden, A.L., Schoepp, D.D., Metabotropic glutamate receptor targets for neuropsychiatric disorders. Drug Discov. Today: Ther. Strat. 3 (2006), 507–517.
213. 213 Wolak, M., et al. Involvement of NMDA and AMPA receptors in the antidepressant-like activity of antidepressant drugs in the forced swim test. Pharmacol. Rep. 65 (2013), 991–997.
214. 214 Maeng, S., et al. Cellular mechanisms underlying the antidepressant effects of ketamine: role of alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid receptors. Biol. Psychiatry 63 (2008), 349–352.
215. 215 Bai, F., et al. Chronic AMPA receptor potentiator (LY451646) treatment increases cell proliferation in adult rat hippocampus. Neuropharmacology 44 (2003), 1013–1021.
216. 216 Kramer, M.S., et al. Demonstration of the efficacy and safety of a novel substance P (NK1) receptor antagonist in major depression. Neuropsychopharmacology 29 (2004), 385–392.
217. 217 Czéh, B., et al. NK1 receptor antagonists under investigation for the treatment of affective disorders. Expert Opin. Investig. Drugs 15 (2006), 479–486.
218. 218 Keller, M., et al. Lack of efficacy of the substance P (neurokinin1 receptor) antagonist aprepitant in the treatment of major depressive disorder. Biol. Psychiatry 59 (2006), 216–223.
219. 219 Gobbi, G., et al. Neurokinin 1 receptor antagonism requires norepinephrine to increase serotonin function. Eur. Neuropsychopharmacol. 17 (2007), 328–338.
220. 220 Ryckmans, T., et al. First dual NK1 antagonists–serotonin reuptake inhibitors: synthesis and SAR of a new class of potential antidepressants. Bioorg. Med. Chem. Lett. 12 (2002), 261–264.
221. 221 Youdim, M.B.H., Buccafusco, J.J., Multi-functional drugs for various CNS targets in the treatment of neurodegenerative disorders. Trends Pharmacol. Sci. 26 (2005), 27–35.
222. 222 Buccafusco, J.J., Terry, A.V. Jr., Multiple CNS targets for eliciting beneficial effects on memory and cognition. J. Pharm. Exp. Ther. 295 (2000), 438–446.
223. 223 Youdim, M.B.H., Why do we need multifunctional neuroprotective and neurorestorative drugs for Parkinson's and Alzheimer's diseases as disease modifying agents. Exp. Neurol. 19 (2010), 1–14.
224. 224 Schapira, A., et al. Rasagiline. Nat. Rev. Drug Discov. 4 (2005), 625–626.
225. 225 Geldenhuys, W.J., et al. The emergence of designed multiple ligands for neurodegenerative disorders. Prog. Neurobiol. 94 (2011), 347–359.
226. 226 Weinreb, O., et al. Neuroprotection via pro-survival protein kinase C isoforms associated with Bcl-2 family members. FASEB J 18 (2004), 1471–1473.
227. 227 Bar-Am, O., et al. Regulation of Bcl-2 family proteins, neurotrophic factors, and APP processing in the neurorescue activity of propargylamine. FASEB J 19 (2005), 1899–1901.
228. 228 Youdim, M.B.H., et al. Rasagiline: neurodegeneration, neuroprotection, and mitochondrial permeability transition. J. Neurosci. Res. 79 (2005), 172–179.
229. 229 Maruyama, W., et al. N-Propargyl-1 (R)-aminoindan, rasagiline, increases glial cell line-derived neurotrophic factor (GDNF) in neuroblastoma SH-SY5Y cells through activation of NF-kappaB transcription factor. Neurochem. Int. 44 (2004), 393–400.
230. 230 Weinreb, O., et al. Induction of neurotrophic factors GDNF and BDNF associated with the mechanism of neurorescue action of rasagiline and ladostigil: new insights and implications for therapy. Ann. N. Y. Acad. Sci. 1122 (2007), 155–168.
231. 231 Mattson, M.P., Pathways towards and away from Alzheimer's disease. Nature 430 (2004), 631–639.
232. 232 Barnham, K.J., et al. Neurodegenerative diseases and oxidative stress. Nat. Rev. Drug Discov. 3 (2004), 205–214.
233. 233 Brown, D.R., Kozlowski, H., Biological inorganic and bioinorganic chemistry of neurodegeneration based on prion and Alzheimer diseases. Dalton Trans. 13 (2004), 1907–1917.
234. 234 Akk, G., Steinbach, J.H., Galantamine activates muscle-type nicotinic acetylcholine receptors without binding to the acetylcholine-binding site. J. Neurosci. 25 (2005), 1992–2001.
235. 235 Dajas-Bailador, F.A., et al. The allosteric potentiation of nicotinic acetylcholine receptors by galantamine is transduced into cellular responses in neurons: Ca2+ signals and neurotransmitter release. Mol. Pharmacol. 64 (2003), 1217–1226.
236. 236 Jiang, H., et al. Benzenediol–berberine hybrids: multifunctional agents for Alzheimer's disease. Bioorg. Med. Chem. 19 (2011), 7228–7235.
237. 237 Ono, K., et al. Potent anti-amyloidogenic and fibril-destabilizing effects of poly phenols in vitro: implications for the prevention and therapeutics of Alzheimer's disease. J. Neurochem. 87 (2003), 172–181.
238. 238 Baur, J.A., Sinclair, D.A., Therapeutic potential of resveratrol: the in vivo evidence. Nat. Rev. Drug Discov. 5 (2006), 493–506.
239. 239 Abraham, J., Johnson, R.W., Consuming a diet supplemented with resveratrol reduced infection-related neuroinflammation and deficits in working memory in aged mice. Rejuvenation Res. 12 (2009), 445–453.
240. 240 Ladiwala, A.R.A., et al. Resveratrol selectively remodels soluble oligomers and fibrils of amyloid aβ into off-pathway conformers. J. Biol. Chem. 285 (2010), 24228–24237.
241. 241 Freeman, S.E., Dawson, R.M., Tacrine: a pharmacological review. Prog. Neurobiol. 36 (1991), 257–277.
242. 242 Mancino, A.M., et al. Effects of clioquinol on metal-triggered amyloid-β aggregation revisited. Inorg. Chem. 48 (2009), 9596–9598.
243. 243 Oz, M., et al. Methylene blue and Alzheimer's disease. Biochem. Pharmacol. 78 (2009), 927–932.
244. 244 Wang, X-Q., et al. Design, synthesis, and biological evaluation of 2-arylethenylquinoline derivatives as multifunctional agents for the treatment of Alzheimer's disease. Eur. J. Med. Chem. 89 (2015), 349–361.
245. 245 Hopkins, A.L., Network pharmacology: the next paradigm in drug discovery. Nat. Chem. Biol. 4 (2008), 682–690.
246. 246 American Psychiatric Association, Diagnostic and Statistical Manual of Mental Disorder (DSM-5). 2013.
247. 247 Nutt, D.J., et al. Phenomenology of anxiety disorders. Blanchard, R.J., Blanchard, D.C., Griebel, G., Nutt, D., (eds.) Handbook of Anxiety and Fear, 2008, Elsevier B.V., Amsterdam, 365–393.
248. 248 Reinhold, J.A., et al. Pharmacological treatment of generalized anxiety disorder. Expert Opin. Pharmacother. 12 (2011), 2457–2467.
249. 249 Ganasen, K.A., Stein, D.J., Pharmacotherapy of social anxiety disorder. Curr. Top. Behav. Neurosci. 2 (2010), 487–503.
250. 250 Jeffreys, M., et al. Pharmacotherapy for posttraumatic stress disorder: review with clinical applications. J. Rehabil. Res. Dev. 49 (2012), 703–715.
251. 251 Stein, M., et al. Pharmacologic treatment of panic disorder. Curr. Top. Behav. Neurosci. 2 (2010), 469–485.
252. 252 Abudy, A., et al. Pharmacological management of treatment-resistant obsessive-compulsive disorder. CNS Drugs 25 (2011), 585–596.
253. 253 Dole, M.N., et al. Development and validation of analytical methods for estimation of desvenlafaxine succinate in bulk and solid dosage forms by UV spectroscopy. Der Pharma Chemica 5 (2013), 270–273.
254. 254 Hou, J., et al. In vitro and in vivo characterization of PA01, a novel promising triple reuptake inhibitor. Physiol. Behav. 138 (2015), 141–149.
255. 255 Shaw, A.M., et al. Antidepressant-like effects of novel triple reuptake inhibitors, PRC025 and PRC050. Eur. J. Pharmacol. 555 (2007), 30–36.
256. 256 Skolnick, P., et al. Antidepressant-like actions of DOV 21,947: a triple reuptake inhibitor. Eur. J. Pharmacol. 461 (2003), 99–104.
257. 257 Maryanoff, B.E., et al. Pyrroloisoquinoline antidepressants. 2. In-depth exploration of structure-activity relationships. J. Med. Chem. 30 (1987), 1433–1454.
258. 258 Aluisio, L., In-vitro and in-vivo characterization of JNJ-7925476, a novel triple monoamine uptake inhibitor. Eur. J. Pharmacol. 587 (2008), 141–146.
259. 259 Xue, R., et al. The discovery of 071031B, a novel serotonin and noradrenaline reuptake inhibitor. Neurosci. Lett. 544 (2013), 68–73.
260. 260 Ben Shachar, D.B., et al. Neuroprotection by a novel brain permeable iron chelator, VK-28, against 6-hydroxydopamine lesion in rats. Neuropharmacology 46 (2004), 254–263.
261. 261 Youdim, M.B., et al. Bifunctional drug derivatives of MAO-B inhibitor rasagiline and iron chelator VK-28 as a more effective approach to treatment of brain ageing and ageing neurodegenerative diseases. Mech. Ageing Dev. 126 (2005), 317–326.
262. 262 Zecca, L., et al. Iron, brain ageing and neurodegenerative disorders. Nat. Rev. Neurosci. 5 (2004), 863–873.
263. 263 Gal, S., et al. 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. 95 (2005), 79–88.
264. 264 Kupershmidt, L., et al. Novel molecular targets of the neuroprotective/neurorescue multimodal iron chelating drug M30 in the mouse brain. Neuroscience 189 (2011), 345–358.
265. 265 Zhu, Y., et al. Neuroprotective agents target molecular mechanisms of disease in ALS. Drug Discov. Today 20 (2015), 65–75.
266. 266 Ben-Shachar, D., Neuroprotection by a novel brain permeable iron chelator, VK-28, against 6-hydroxydopamine lession in rats. Neuropharmacology 46 (2004), 254–263.
267. 267 Zheng, H., et al. Design, synthesis, and evaluation of novel bifunctional iron-chelators as potential agents for neuroprotection in Alzheimer's, Parkinson's, and other neurodegenerative diseases. Bioorg. Med. Chem. 13 (2005), 773–783.
268. 268 Zheng, H., et al. Novel potential neuroprotective agents with both iron chelating and amino acid-based derivatives targeting central nervous system neurons. Biochem. Pharmacol. 70 (2005), 1642–1652.
269. 269 Weinstock, M., et al. TV3326, a novel neuroprotective drug with cholinesterase and monoamine oxidase inhibitory activities for the treatment of Alzheimer's disease. J. Neural Transm. Suppl. 60 (2000), 157–169.
270. 270 Youdim, M.B.H., et al. Rasagiline [N-propargyl-1R(+)-aminoindan], a selective and potent inhibitor of mitochondrial monoamine oxidase B. Br. J. Pharmacol. 132 (2001), 500–506.
271. 271 Weinstock, M., et al. Effect of TV3326, a novel monoamine oxidase cholinesterase inhibitor, in rat models of anxiety and depression. Psychopharmacology 160 (2002), 318–324.
272. 272 Buccafusco, J.J., et al. Potential cognitive actions of (N-propargyl-(3R)-aminoindan-5-yl)-ethyl, methyl carbamate (tv3326), a novel neuroprotective agent, as assessed in old rhesus monkeys in their performance of versions of a delayed matching task. Neuroscience 119 (2003), 669–678.
273. 273 Sagi, Y., et al. Attenuation of MPTP-induced dopaminergic neurotoxicity by TV3326, a cholinesterase-monoamine oxidase inhibitor. J. Neurochem. 86 (2003), 290–297.
274. 274 Weinstock, M., et al. A novel cholinesterase and brain-selective monoamine oxidase inhibitor for the treatment of dementia comorbid with depression and Parkinson's disease. Prog. Neuropsychopharmacol. Biol. Psychiatry 27 (2003), 555–561.
275. 275 Youdim, M.B.H., Rasagiline; an anti-parkinson drug with neuroprotective activity. Expert Rev. Neurother. 3 (2003), 737–749.
276. 276 Weinreb, O., et al. A novel anti-Alzheimer's disease drug, ladostigil: neuroprotective multimodal brain-selective monoamine-oxidase and cholinesterase inhibitor. Youdim, M., Riederer, P., (eds.) International Review of Neurobiology, Monoamine Oxidase and Their Inhibitors, 2011, Elsevier, 193–209.
277. 277 LeWitt, P.A., et al. Adenosine A2A receptor antagonist istradefylline (KW-6002) reduces “off” time in Parkinson's disease: a double-blind, randomized, multicenter clinical trial (6002-US-005). Ann. Neurol. 63 (2008), 295–302.
278. 278 Fernandez, H.H., et al. Istradefylline as monotherapy for Parkinson disease: results of the 6002-US-051 trial. Parkinsonism Relat. Disord. 16 (2010), 16–20.
279. 279 Jenner, P., et al. Adenosine, adenosine A 2A antagonists, and Parkinson's disease. Parkinsonism Relat. Disord. 15 (2009), 406–413.
280. 280 Morelli, M., et al. Adenosine A2A receptors and Parkinson's disease. Handb. Exp. Pharmacol. 193 (2009), 589–615.
281. 281 Jain, K.K., Evaluation of memantine for neuroprotection in dementia. Expert Opin. Investig. Drugs 9 (2000), 1397–1406.
282. 282 Li, L., et al. Memantine inhibits and reverses the Alzheimer type abnormal hyperphosphorylation of tau and associated neurodegeneration. FEBS Lett. 566 (2004), 261–269.
283. 283 Song, M.S., et al. Memantine protects rat cortical cultured neurons against beta-amyloid-induced toxicity by attenuating tau phosphorylation. Eur. J. Neurosci. 28 (2008), 1989–2002.
284. 284 Zdanys, K., Tampi, R.R., A systematic review of off-label uses of memantine for psychiatric disorders. Prog. Neuropsychopharmacol. Biol. Psychiatry 32 (2008), 1362–1374.
285. 285 Kiewert, C., et al. NGP 1-01 is a brain-permeable dual blocker of neuronal voltage- and ligand-operated calcium channels. Neurochem. Res. 31 (2006), 395–399.
286. 286 Hao, J., et al. Neuroprotection in mice by NGP 1-01 after transient focal brain ischemia. Brain Res. 1196 (2008), 113–120.
287. 287 Lockman, J.A., et al. NGP 1-01, a multi-targeted polycyclic cage amine, attenuates brain endothelial cell death in iron overload conditions. Brain Res. 1489 (2012), 133–139.
288. 288 Yan, Q., et al. Anti-inflammatory drug therapy alters beta-amyloid processing and deposition in an animal model of Alzheimer's disease. J. Neurosci. 23 (2003), 7504–7509.
289. 289 Heneka, M.T., et al. Acute treatment with the PPAR-gamma agonist pioglitazone and ibuprofen reduces glial inflammation and Abeta1-42 levels in APPV717I transgenic mice. Brain 128 (2005), 1442–1453.
290. 290 Culman, J., et al. PPAR-gamma: therapeutic target for ischemic stroke. Trends Pharmacol. Sci. 28 (2007), 244–249.
291. 291 Ji, S., et al. Acute neuroprotection by pioglitazone after mild brain ischemia without effect on long-term outcome. Exp. Neurol. 216 (2009), 321–328.
292. 292 Kaundal, R.K., et al. Protective effects of pioglitazone against global cerebral ischemic-reperfusion injury in gerbils. J. Pharmacol. Sci. 109 (2009), 361–367.
293. 293 Quinn, L.P., et al. The PPARgamma agonist pioglitazone is effective in the MPTP mouse model of Parkinson's disease through inhibition of monoamine oxidase B. Br. J. Pharmacol. 154 (2008), 226–233.
294. 294 Chen, Y.F., et al. Cisd2 mediates mitochondrial integrity and life span in mammals. Autophagy 5 (2009), 1043–1045.
295. 295 Wang, L., et al. Donepezil + propargylamine + 8-hydroxyquinoline hybrids as new multifunctional metal-chelators, ChE and MAO inhibitors for the potential treatment of Alzheimer's disease. Eur. J. Med. Chem. 80 (2014), 543–561.
296. 296 Liu, J., et al. Synthesis and characterization of 1H-phenanthro[9,10-d]imidazole derivatives as multifunctional agents for treatment of Alzheimer's disease. Biochim. Biophys. Acta 1840 (2014), 2886–2903.
297. 297 Pudlo, M., et al. Quinolone–benzylpiperidine derivatives as novel acetylcholinesterase inhibitor and antioxidant hybrids for Alzheimer disease. Bioorg. Med. Chem. 22 (2014), 2496–2507.
298. 298 Bautista-Aguilera, O.M., et al. Design, synthesis, pharmacological evaluation, QSAR analysis, molecular modeling and ADMET of novel donepezil–indolyl hybrids as multipotent cholinesterase/monoamine oxidase inhibitors for the potential treatment of Alzheimer's disease. Eur. J. Med. Chem. 75 (2014), 82–95.
299. 299 Li, Y., et al. Design, synthesis and evaluation of rivastigmine and curcumin hybrids as site-activated multitarget-directed ligands for Alzheimer's disease therapy. Bioorg. Med. Chem. 22 (2014), 4717–4725.
300. 300 Chen, Y., et al. Design, synthesis and evaluation of tacrine–flurbiprofen–nitrate trihybrids as novel anti-Alzheimer's disease agents. Bioorg. Med. Chem. 21 (2013), 2462–2470.
301. 301 Mao, F., et al. O-Hydroxyl- or o-amino benzylamine–tacrine hybrids: multifunctional biometals chelators, antioxidants, and inhibitors of cholinesterase activity and amyloid-β aggregation. Bioorg. Med. Chem. 20 (2012), 5884–5892.
302. 302 Minarini, A., et al. Cystamine-tacrine dimer: a new multi-target-directed ligand as potential therapeutic agent for Alzheimer's disease treatment. Neuropharmacology 62 (2012), 997–1003.
303. 303 Huang, L., et al. Inhibition of cholinesterase activity and amyloid aggregation by berberine–phenyl–benzoheterocyclic and tacrine–phenyl–benzoheterocyclic hybrids. Bioorg. Med. Chem. 20 (2012), 3038–3048.
304. 304 Fernández-Bachiller, M.L., et al. Novel tacrine-8-hydroxyquinoline hybrids as multifunctional agents for the treatment of Alzheimer's disease, with neuroprotective, cholinergic, antioxidant, and copper-complexing properties. J. Med. Chem. 53 (2010), 4927–4937.
305. 305 Antequera, D., et al. Effects of a tacrine-8-hydroxyquinoline hybrid (IQM-622) on Aβ accumulation and cell death: involvement in hippocampal neuronal loss in Alzheimer's disease. Neurobiol. Dis. 46 (2012), 682–691.
306. 306 Chao, X., et al. Design, synthesis and pharmacological evaluation of novel tacrine–caffeic acid hybrids as multi-targeted compounds against Alzheimer's disease. Bioorg. Med. Chem. Lett. 22 (2012), 6498–6502.
307. 307 Rodríguez-Franco, M.I., et al. Novel tacrine–melatonin hybrids as dual-acting drugs for Alzheimer disease, with improved acetylcholinesterase inhibitory and antioxidant properties. J. Med. Chem. 49 (2006), 459–462.
308. 308 Fernández-Bachiller, M.L., et al. Tacrine–melatonin hybrids as multifunctional agents for Alzheimer's disease, with cholinergic, antioxidant, and neuroprotective properties. ChemMedChem 4 (2009), 828–841.