New pharmacological avenues for the treatment of l-DOPA-induced dyskinesias in Parkinson's disease: Targeting glutamate and adenosine receptors

Expert Opinion on Investigational Drugs

Volumn 21, Issue 2, 2012, Pages 153-168

  Blandini, Fabio ^a   Armentero, Marie Therese ^a  

^a C MONDINO NATIONAL NEUROLOGICAL INSTITUTE   (Italy)

Author keywords

Adenosine; Dyskinesias; Glutamate; l DOPA; MGluR5; NMDA; Parkinson's disease

Indexed keywords

ADENOSINE A2A RECEPTOR; ADENOSINE RECEPTOR; AMANTADINE; ANTIPARKINSON AGENT; APOMORPHINE; AX 48621; CARBIDOPA PLUS LEVODOPA; ENTACAPONE; GLUTAMATE RECEPTOR; ISTRADEFYLLINE; LEVODOPA; LISURIDE; METABOTROPIC RECEPTOR 5; N METHYL DEXTRO ASPARTIC ACID RECEPTOR; OCTAHYDRO 4 HYDROXY 4 [(3 METHYLPHENYL)ETHYNYL] 1H INDOLE 1 CARBOXYLIC ACID METHYL ESTER; PERAMPANEL; PLACEBO; PRAMIPEXOLE; PRELADENANT; ROPINIROLE; ST 1535; TALAMPANEL; TOZADENANT; UNCLASSIFIED DRUG; VIPADENANT;

CLINICAL FEATURE; CORPUS STRIATUM; DOSE RESPONSE; DRUG POTENTIATION; DYSKINESIA; HUMAN; MOLECULAR MECHANICS; NERVE CELL; NERVE CELL PLASTICITY; NONHUMAN; PARKINSON DISEASE; PROTEIN EXPRESSION; REVIEW;

ANIMALS; ANTIPARKINSON AGENTS; DYSKINESIAS; EXCITATORY AMINO ACID ANTAGONISTS; HUMANS; LEVODOPA; PARKINSON DISEASE; PURINERGIC P1 RECEPTOR ANTAGONISTS; RECEPTORS, GLUTAMATE; RECEPTORS, PURINERGIC P1;

EID: 84855814440     PISSN: 13543784     EISSN: 17447658     Source Type: Journal    
DOI: 10.1517/13543784.2012.651457     Document Type: Review

References (128)

1. Betarbet R, Sherer TB, Di Monte DA, Greenamyre JT. Mechanistic approaches to Parkinson's disease pathogenesis. Brain Pathol 2002;21:499-510 (Pubitemid 35154938)
2. Bonifati V, Oostra BA, Heutink P. Unraveling the pathogenesis of Parkinson's disease-the contribution of monogenic forms. Cell Mol Life Sci 2004;61:1729-50 (Pubitemid 39044252)
3. Hirsch EC. Mechanism and consequences of nerve cell death in Parkinson's disease. J Neural Transm Suppl 1999;56:127-37 (Pubitemid 29242874)
4. Jellinger KA. Neuropathology of movement disorders. Neurosurg Clin N Am 1998;9:237-62 (Pubitemid 28169299)
5. Riederer P, Lange KW. Pathogenesis of Parkinson's disease. Curr Opin Neurol Neurosurg 1992;5:295-300
6. Schapira AH, Gu M, Taanman JW, et al. Mitochondria in the etiology and pathogenesis of Parkinson's disease. Ann Neurol 1998;44:S89-98 (Pubitemid 28423834)
7. Blandini F, Nappi G, Tassorelli C, Martignoni E. Functional changes of the basal ganglia circuitry in Parkinson's disease. Prog Neurobiol 2000;62:63-88 (Pubitemid 30252017)
8. Jellinger KA. Pathology of Parkinson's disease. Changes other than the nigrostriatal pathway. Mol Chem Neuropathol 1991;14:153-97
9. Poewe W. Non-motor symptoms in Parkinson's disease. Eur J Neurol 2008;15(Suppl 1):14-20 (Pubitemid 351421304)
10. Gasser T, Hardy J, Mizuno Y. Milestones in PD genetics. Mov Disord 2011;26:1042-8
11. Obeso JA, Olanow CW, Nutt JG. Levodopa motor complications in Parkinson's disease. Trends Neurosci 2000;23:S2-7
12. Gottwald MD, Aminoff MJ. Therapies for dopaminergic-induced dyskinesias in Parkinson disease. Ann Neurol 2011;69:919-27
13. Rascol O. Drugs and drug delivery in PD: optimizing control of symptoms with pramipexole prolonged-release. Eur J Neurol 2011;18(Suppl 1):3-10
14. Antonini A, Odin P. Pros and cons of apomorphine and L-dopa continuous infusion in advanced Parkinson's disease. Parkinsonism Relat Disord 2009;15(Suppl 4):S97-100
15. Stocchi F, Rascol O, Kieburtz K, et al. Initiating levodopa/carbidopa therapy with and without entacapone in early Parkinson disease: the STRIDE-PD study. Ann Neurol 2010;68:18-27
16. Kuoppamaki M, Korpela K, Marttila R, et al. Comparison of pharmacokinetic profile of levodopa throughout the day between levodopa/carbidopa/entacapone and levodopa/carbidopa when administered four or five times daily. Eur J Clin Pharmacol 2009;65:443-55
17. Nutt JG. Effect of COMT inhibition on the pharmacokinetics and pharmacodynamics of levodopa in parkinsonian patients. Neurology 2000;55:S33-7
18. Nyholm D, Askmark H, Aquilonius SM. Stalevo reduction in dyskinesia evaluation in Parkinson's disease results were expected from a pharmacokinetic viewpoint. Ann Neurol 2011;69:424
19. Limousin P, Krack P, Pollak P, et al. Electrical stimulation of the subthalamic nucleus in advanced Parkinson's disease. N Engl J Med 1998;339:1105-11 (Pubitemid 28465758)
20. Benabid AL, Chabardes S, Mitrofanis J, Pollak P. Deep brain stimulation of the subthalamic nucleus for the treatment of Parkinson's disease. Lancet Neurol 2009;8:67-81
21. Durif F, Deffond D, Dordain G, Tournilhac M. Apomorphine and diphasic dyskinesia. Clin Neuropharmacol 1994;17:99-102 (Pubitemid 24046714)
22. Hely MA, Morris JG, Reid WG, et al. The Sydney Multicentre Study of Parkinson's disease: a randomised, prospective five year study comparing low dose bromocriptine with low dose levodopa-carbidopa. J Neurol Neurosurg Psychiatry 1994;57:903-10 (Pubitemid 24251051)
23. Poewe WH, Lees AJ, Stern GM. Low-dose L-dopa therapy in Parkinson's disease: a 6-year follow-up study. Neurology 1986;36:1528-30 (Pubitemid 17175783)
24. Fabbrini G, Brotchie JM, Grandas F, et al. Levodopa-induced dyskinesias. Mov Disord 2007;22:1379-89 (Pubitemid 47280623)
25. Schrag A, Hovris A, Morley D, et al. Young-versus older-onset Parkinson's disease: impact of disease and psychosocial consequences. Mov Disord 2003;18:1250-6 (Pubitemid 38263307)
26. Zappia M, Annesi G, Nicoletti G, et al. Sex differences in clinical and genetic determinants of levodopa peak-dose dyskinesias in Parkinson disease: an exploratory study. Arch Neurol 2005;62:601-5 (Pubitemid 40489893)
27. Pechevis M, Clarke CE, Vieregge P, et al. Effects of dyskinesias in Parkinson's disease on quality of life and health-related costs: a prospective European study. Eur J Neurol 2005;12:956-63 (Pubitemid 41820050)
28. Di Monte DA, McCormack A, Petzinger G, et al. Relationship among nigrostriatal denervation, parkinsonism, and dyskinesias in the MPTP primate model. Mov Disord 2000;15:459-66 (Pubitemid 30333216)
29. Lundblad M, Picconi B, Lindgren H, Cenci MA. A model of L-DOPA-induced dyskinesia in 6-hydroxydopamine lesioned mice: relation to motor and cellular parameters of nigrostriatal function. Neurobiol Dis 2004;16:110-23 (Pubitemid 38569802)
30. Paille V, Brachet P, Damier P. Role of nigral lesion in the genesis of dyskinesias in a rat model of Parkinson's disease. Neuroreport 2004;15:561-4 (Pubitemid 38328160)
31. Carta M, Carlsson T, Kirik D, Bjorklund A. Dopamine released from 5-HT terminals is the cause of L-DOPA-induced dyskinesia in parkinsonian rats. Brain 2007;130:1819-33 (Pubitemid 47343795)
32. Tanaka H, Kannari K, Maeda T, et al. Role of serotonergic neurons in L-DOPA-derived extracellular dopamine in the striatum of 6-OHDA-lesioned rats. Neuroreport 1999;10:631-4 (Pubitemid 29333295)
33. Pavese N, Evans AH, Tai YF, et al. Clinical correlates of levodopa-induced dopamine release in Parkinson disease: a PET study. Neurology 2006;67:1612-17 (Pubitemid 44747932)
34. Lee J, Zhu WM, Stanic D, et al. Sprouting of dopamine terminals and altered dopamine release and uptake in Parkinsonian dyskinaesia. Brain 2008;131:1574-87 (Pubitemid 351806467)
35. Calon F, Hadj TA, Blanchet PJ, et al. Dopamine-receptor stimulation: biobehavioral and biochemical consequences. Trends Neurosci 2000;23:S92-100
36. Linazasoro G. New ideas on the origin of L-dopa-induced dyskinesias: age, genes and neural plasticity. Trends Pharmacol Sci 2005;26:391-7. (Pubitemid 41039214)
37. Picconi B, Centonze D, Hakansson K, et al. Loss of bidirectional striatal synaptic plasticity in L-DOPA-induced dyskinesia. Nat Neurosci 2003;6:501-6. (Pubitemid 36514698)
38. Picconi B, Paille V, Ghiglieri V, et al. l-DOPA dosage is critically involved in dyskinesia via loss of synaptic depotentiation. Neurobiol Dis 2008;29:327-35
39. Bezard E, Brotchie JM, Gross CE. Pathophysiology of levodopa-induced dyskinesia: potential for new therapies. Nat Rev Neurosci 2001;2:577-88 (Pubitemid 33679831)
40. Aubert I, Guigoni C, Hakansson K, et al. Increased D1 dopamine receptor signaling in levodopa-induced dyskinesia. Ann Neurol 2005;57:17-26 (Pubitemid 40053311)
41. Hakansson K, Lindskog M, Pozzi L, et al. DARPP-32 and modulation of cAMP signaling: involvement in motor control and levodopa-induced dyskinesia. Parkinsonism Relat Disord 2004;10:281-6 (Pubitemid 38757808)
42. Konradi C, Westin JE, Carta M, et al. Transcriptome analysis in a rat model of L-DOPA-induced dyskinesia. Neurobiol Dis 2004;17:219-36 (Pubitemid 39345778)
43. Santini E, Valjent E, Usiello A, et al. Critical involvement of cAMP/DARPP-32 and extracellular signal-regulated protein kinase signaling in L-DOPA-induced dyskinesia. J Neurosci 2007;27:6995-7005 (Pubitemid 47015907)
44. Santini E, Sgambato-Faure V, Li Q, et al. Distinct changes in cAMP and extracellular signal-regulated protein kinase signalling in L-DOPA-induced dyskinesia. PLoS ONE 2010;5:e12322.
45. Bychkov E, Ahmed MR, Dalby KN, Gurevich EV. Dopamine depletion and subsequent treatment with L-DOPA, but not the long-lived dopamine agonist pergolide, enhances activity of the Akt pathway in the rat striatum. J Neurochem 2007;102:699-711 (Pubitemid 47057295)
46. Lebel M, Chagniel L, Bureau G, Cyr M. Striatal inhibition of PKA prevents levodopa-induced behavioural and molecular changes in the hemiparkinsonian rat. Neurobiol Dis 2010;38:59-67
47. Morissette M, Samadi P, Hadj TA, et al. Striatal Akt/GSK3 signaling pathway in the development of L-Dopa-induced dyskinesias in MPTP monkeys. Prog Neuropsychopharmacol Biol Psychiatry 2010;34:446-54
48. Ding Y, Won L, Britt JP, et al. Enhanced striatal cholinergic neuronal activity mediates L-DOPA-induced dyskinesia in parkinsonian mice. Proc Natl Acad Sci USA 2011;108:840-5
49. Dingledine R, Conn PJ. Peripheral glutamate receptors: molecular biology and role in taste sensation. J Nutr 2000;130:1039S-1042S (Pubitemid 30173640)
50. Paoletti P, Neyton J. NMDA receptor subunits: function and pharmacology. Curr Opin Pharmacol 2007;7:39-47 (Pubitemid 46238036)
51. Greger IH, Ziff EB, Penn AC. Molecular determinants of AMPA receptor subunit assembly. Trends Neurosci 2007;30:407-16 (Pubitemid 47088718)
52. Huettner JE. Kainate receptors and synaptic transmission. Prog Neurobiol 2003;70:387-407 (Pubitemid 37159280)
53. Nakanishi S. Metabotropic glutamate receptors: synaptic transmission, modulation, and plasticity. Neuron 1994;13:1031-7 (Pubitemid 24372123)
54. Lujan-Miras R. Metabotropic glutamate receptors: new molecular targets in the treatment of neurological and psychiatric diseases. Rev Neurol 2005;40:43-53 (Pubitemid 41295377)
55. Hallett PJ, Dunah AW, Ravenscroft P, et al. Alterations of striatal NMDA receptor subunits associated with the development of dyskinesia in the MPTP-lesioned primate model of Parkinson's disease. Neuropharmacology 2005;48:503-16 (Pubitemid 40332408)
56. Gardoni F, Picconi B, Ghiglieri V, et al. A critical interaction between NR2B and MAGUK in L-DOPA induced dyskinesia. J Neurosci 2006;26:2914-22
57. Nash JE, Ravenscroft P, McGuire S, et al. The NR2B-selective NMDA receptor antagonist CP-101,606 exacerbates L-DOPA-induced dyskinesia and provides mild potentiation of anti-parkinsonian effects of L-DOPA in the MPTP-lesioned marmoset model of Parkinson's disease. Exp Neurol 2004;188:471-9 (Pubitemid 38891607)
58. Gardoni F, Sgobio C, Pendolino V, et al. Targeting NR2A-containing NMDA receptors reduces L-DOPA-induced dyskinesias. Neurobiol Aging 2011[Epub ahead of print]
59. Oh JD, Chase TN. Glutamate-mediated striatal dysregulation and the pathogenesis of motor response complications in Parkinson's disease. Amino Acids 2002;23:133-9
60. Ahmed I, Bose SK, Pavese N, et al. Glutamate NMDA receptor dysregulation in Parkinson's disease with dyskinesias. Brain 2011;134:979-86
61. Luginger E, Wenning GK, Bosch S, Poewe W. Beneficial effects of amantadine on L-dopa-induced dyskinesias in Parkinson's disease. Mov Disord 2000;15:873-8
62. Verhagen ML, Del Dotto P, van den MP, et al. Amantadine as treatment for dyskinesias and motor fluctuations in Parkinson's disease. Neurology 1998;50:1323-6 (Pubitemid 28240346)
63. Crosby NJ, Deane KH, Clarke CE. Amantadine for dyskinesia in Parkinson's disease. Cochrane Database Syst Rev 2003;CD003467
64. Snow BJ, Macdonald L, Mcauley D, Wallis W. The effect of amantadine on levodopa-induced dyskinesias in Parkinson's disease: a double-blind, placebo-controlled study. Clin Neuropharmacol 2000;23:82-5 (Pubitemid 30212217)
65. Wolf E, Seppi K, Katzenschlager R, et al. Long-term antidyskinetic efficacy of amantadine in Parkinson's disease. Mov Disord 2010;25:1357-63
66. Sawada H, Oeda T, Kuno S, et al. Amantadine for dyskinesias in Parkinson's disease: a randomized controlled trial. PLoS One 2010;5:e15298
67. Nutt JG, Gunzler SA, Kirchhoff T, et al. Effects of a NR2B selective NMDA glutamate antagonist, CP-101,606, on dyskinesia and Parkinsonism. Mov Disord 2008;23:1860-6
68. Nash JE, Ravenscroft P, McGuire S, et al. The NR2B-selective NMDA receptor antagonist CP-101,606 exacerbates L-DOPA-induced dyskinesia and provides mild potentiation of anti-parkinsonian effects of L-DOPA in the MPTP-lesioned marmoset model of Parkinson's disease. Exp Neurol 2004;188:471-9 (Pubitemid 38891607)
69. Kobylecki C, Cenci MA, Crossman AR, Ravenscroft P. Calcium-permeable AMPA receptors are involved in the induction and expression of l-DOPA-induced dyskinesia in Parkinson's disease. J Neurochem 2010;114:499-511
70. Ouattara B, Hoyer D, Gregoire L, et al. Changes of AMPA receptors in MPTP monkeys with levodopa-induced dyskinesias. Neuroscience 2010;167:1160-7
71. Konitsiotis S, Blanchet PJ, Verhagen L, et al. AMPA receptor blockade improves levodopa-induced dyskinesia in MPTP monkeys. Neurology 2000;54:1589-95 (Pubitemid 30226801)
72. Eggert K, Squillacote D, Barone P, et al. Safety and efficacy of perampanel in advanced Parkinson's disease: a randomized, placebo-controlled study. Mov Disord 2010;25:896-905
73. Conn PJ, Battaglia G, Marino MJ, Nicoletti F. Metabotropic glutamate receptors in the basal ganglia motor circuit. Nat Rev Neurosci 2005;6:787-98 (Pubitemid 41679241)
74. Samadi P, Gregoire L, Morissette M, et al. mGluR5 metabotropic glutamate receptors and dyskinesias in MPTP monkeys. Neurobiol Aging 2008;29:1040-51 (Pubitemid 351697993)
75. Ouattara B, Gregoire L, Morissette M, et al. Metabotropic glutamate receptor type 5 in levodopa-induced motor complications. Neurobiol Aging 2011;32:1286-95
76. Johnston TH, Fox SH, McIldowie MJ, et al. Reduction of L-DOPA-induced dyskinesia by the selective metabotropic glutamate receptor 5 antagonist 3-[(2-methyl-1,3-thiazol-4-yl)ethynyl]pyridine in the 1-methyl-4-phenyl-1,2,3,6- tetrahydropyridine-lesioned macaque model of Parkinson's disease. J Pharmacol Exp Ther 2010;333:865-73
77. Levandis G, Bazzini E, Armentero MT, et al. Systemic administration of an mGluR5 antagonist, but not unilateral subthalamic lesion, counteracts l-DOPA-induced dyskinesias in a rodent model of Parkinson's disease. Neurobiol Dis 2008;29:161-8. (Pubitemid 350180490)
78. Marin C, Bonastre M, Aguilar E, Jimenez A. The metabotropic glutamate receptor antagonist 2-methyl-6-(phenylethynyl) pyridine decreases striatal VGlut2 expression in association with an attenuation of L-dopa-induced dyskinesias. Synapse 2011;65:1080-6
79. Rylander D, Recchia A, Mela F, et al. Pharmacological modulation of glutamate transmission in a rat model of L-DOPA-induced dyskinesia: effects on motor behavior and striatal nuclear signaling. J Pharmacol Exp Ther 2009;330:227-35
80. Yamamoto N, Soghomonian JJ. Metabotropic glutamate mGluR5 receptor blockade opposes abnormal involuntary movements and the increases in glutamic acid decarboxylase mRNA levels induced by l-DOPA in striatal neurons of 6-hydroxydopamine-lesioned rats. Neuroscience 2009;163:1171-80
81. Gregoire L, Morin N, Ouattara B, et al. The acute antiparkinsonian and antidyskinetic effect of AFQ056, a novel metabotropic glutamate receptor type 5 antagonist, in L-Dopa-treated parkinsonian monkeys. Parkinsonism Relat Disord 2011;17:270-6
82. Berg D, Godau J, Trenkwalder C, et al. AFQ056 treatment of levodopa-induced dyskinesias: results of 2 randomized controlled trials. Mov Disord 2011;26:1243-50
83. Fredholm BB, AP IJ, Jacobson KA, et al. International Union of Pharmacology. XXV. Nomenclature and classification of adenosine receptors. Pharmacol Rev 2001;53:527-52
84. Fredholm BB, AP IJ, Jacobson KA, et al. International Union of Basic and Clinical Pharmacology. LXXXI. Nomenclature and classification of adenosine receptors-an update. Pharmacol Rev 2011;63:1-34
85. Rosin DL, Robeva A, Woodard RL, et al. Immunohistochemical localization of adenosine A2A receptors in the rat central nervous system. J Comp Neurol 1998;401:163-86 (Pubitemid 28481960)
86. Jenner P, Mori A, Hauser R, et al. Adenosine, adenosine A 2A antagonists, and Parkinson's disease. Parkinsonism Relat Disord 2009;15:406-13
87. Morelli M, Carta AR, Jenner P. Adenosine A2A receptors and Parkinson's disease. Handb Exp Pharmacol 2009;193:589-615.
88. Ferre S, Quiroz C, Woods AS, et al. An update on adenosine A2A-dopamine D2 receptor interactions: implications for the function of G protein-coupled receptors. Curr Pharm Des 2008;14:1468-74 (Pubitemid 351997812)
89. Tozzi A, de Iure A, Di Filippo M, et al. The distinct role of medium spiny neurons and cholinergic interneurons in the D/AA receptor interaction in the striatum: implications for Parkinson's disease. J Neurosci 2011;31:1850-62
90. Agnati LF, Guidolin D, Albertin G, et al. An integrated view on the role of receptor mosaics at perisynaptic level: focus on adenosine A(2A), dopamine D(2), cannabinoid CB(1), and metabotropic glutamate mGlu(5) receptors. J Recept Signal Transduct Res 2010;30:355-69
91. Orru M, Bakesova J, Brugarolas M, et al. Striatal pre-and postsynaptic profile of adenosine A(2A) receptor antagonists. PLoS One 2011;6:e16088.
92. Costa J, Lunet N, Santos C, et al. Caffeine exposure and the risk of Parkinson's disease: a systematic review and meta-analysis of observational studies. J Alzheimers Dis 2010;20(Suppl 1):S221-38
93. Shiozaki S, Ichikawa S, Nakamura J, et al. Actions of adenosine A2A receptor antagonist KW-6002 on drug-induced catalepsy and hypokinesia caused by reserpine or MPTP. Psychopharmacology (Berl) 1999;147:90-5 (Pubitemid 30010028)
94. Koga K, Kurokawa M, Ochi M, et al. Adenosine A(2A) receptor antagonists KF17837 and KW-6002 potentiate rotation induced by dopaminergic drugs in hemi-Parkinsonian rats. Eur J Pharmacol 2000;408:249-55
95. Kase H, Aoyama S, Ichimura M, et al. Progress in pursuit of therapeutic A2A antagonists: the adenosine A2A receptor selective antagonist KW6002: research and development toward a novel nondopaminergic therapy for Parkinson's disease. Neurology 2003;61:S97-100 (Pubitemid 37505557)
96. Lundblad M, Vaudano E, Cenci MA. Cellular and behavioural effects of the adenosine A2a receptor antagonist KW-6002 in a rat model of l-DOPA-induced dyskinesia. J Neurochem 2003;84:1398-410 (Pubitemid 36343606)
97. Ochi M, Koga K, Kurokawa M, et al. Systemic administration of adenosine A (2A) receptor antagonist reverses increased GABA release in the globus pallidus of unilateral 6-hydroxydopamine-lesioned rats: a microdialysis study. Neuroscience 2000;100:53-62 (Pubitemid 30670301)
98. Kanda T, Jackson MJ, Smith LA, et al. Adenosine A2A antagonist: a novel antiparkinsonian agent that does not provoke dyskinesia in parkinsonian monkeys. Ann Neurol 1998;43:507-13 (Pubitemid 28231727)
99. Kanda T, Jackson MJ, Smith LA, et al. Combined use of the adenosine A(2A) antagonist KW-6002 with L-DOPA or with selective D1 or D2 dopamine agonists increases antiparkinsonian activity but not dyskinesia in MPTP-treated monkeys. Exp Neurol 2000;162:321-7 (Pubitemid 30217727)
100. Grondin R, Bedard PJ, Hadj Tahar A, et al. Antiparkinsonian effect of a new selective adenosine A2A receptor antagonist in MPTP-treated monkeys. Neurology 1999;52:1673-7 (Pubitemid 29220647)
101. Bibbiani F, Oh JD, Petzer JP, et al. A2A antagonist prevents dopamine agonist-induced motor complications in animal models of Parkinson's disease. Exp Neurol 2003;184:285-94 (Pubitemid 37444038)
102. Rao N, Uchimura T, Mori A. Evaluation of safety, tolerability, and multiple-dose pharmacokinetics of istradefylline in healthy subjects. Clin Parmacol Ther. 2008;83(Suppl):S99
103. Rao N, Uchimura T, Mori A. Evaluation of safety, tolerability, and multiple-dose pharmacokinetics of istradefylline in Parkinson' disease patients. Clin Parmacol Ther.2008;83(Suppl):S99
104. Brooks DJ, Doder M, Osman S, et al. Positron emission tomography analysis of [11C]KW-6002 binding to human and rat adenosine A2A receptors in the brain. Synapse 2008;62:671-81 (Pubitemid 352032542)
105. Bara-Jimenez W, Sherzai A, Dimitrova T, et al. Adenosine A(2A) receptor antagonist treatment of Parkinson's disease. Neurology 2003;61:293-6 (Pubitemid 36975954)
106. Hauser RA, Hubble JP, Truong DD. Randomized trial of the adenosine A(2A) receptor antagonist istradefylline in advanced PD. Neurology 2003;61:297-303 (Pubitemid 36975955)
107. LeWitt PA, Guttman M, Tetrud JW, 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 2008;63:295-302 (Pubitemid 351499859)
108. Stacy M, Silver D, Mendis T, et al. A 12-week, placebo-controlled study (6002-US-006) of istradefylline in Parkinson disease. Neurology 2008;70:2233-40
109. Hauser RA, Shulman LM, Trugman JM, et al. Study of istradefylline in patients with Parkinson's disease on levodopa with motor fluctuations. Mov Disord 2008;23:2177-85
110. Guttman M, Group US. Efficacy of istradefylline in Parkinson's disease patients treated with levodopa with motor-response complications: results of the KW-6002-US-018 study. Mov Disord 2006;21(S15):S585
111. Factor S, Mark MH, Watts R, et al. A long-term study of istradefylline in subjects with fluctuating Parkinson's disease. Parkinsonism Relat Disord 2010;16:423-6
112. Mizuno Y, Hasegawa K, Kondo T, et al. Clinical efficacy of istradefylline (KW-6002) in Parkinson's disease: a randomized, controlled study. Mov Disord 2010;25:1437-43
113. Fernandez HH, Greeley DR, Zweig RM, et al. Istradefylline as monotherapy for Parkinson disease: results of the 6002-US-051 trial. Parkinsonism Relat Disord 2010;16:16-20
114. Hodgson RA, Bertorelli R, Varty GB, et al. Characterization of the potent and highly selective A2A receptor antagonists preladenant and SCH 412348 [7-[2-[4-2,4-difluorophenyl]-1-piperazinyl]ethyl]-2-(2-furanyl)-7H-pyrazol o[4,3-e][1,2,4] triazolo[1,5-c]pyrimidin-5-amine] in rodent models of movement disorders and depression. J Pharmacol Exp Ther 2009;330:294-303
115. Neustadt BR, Hao J, Lindo N, et al. Potent, selective, and orally active adenosine A2A receptor antagonists: arylpiperazine derivatives of pyrazolo[4,3-e]-1,2,4-triazolo[1,5-c]pyrimidines. Bioorg Med Chem Lett 2007;17:1376-80 (Pubitemid 46240836)
116. Hodgson RA, Bedard PJ, Varty GB, et al. Preladenant, a selective A(2A) receptor antagonist, is active in primate models of movement disorders. Exp Neurol 2010;225:384-90
117. Hauser RA, Cantillon M, Pourcher E, et al. Preladenant in patients with Parkinson's disease and motor fluctuations: a phase 2, double-blind, randomised trial. Lancet Neurol 2011;10:221-9
118. Black KJ, Koller JM, Campbell MC, et al. Quantification of indirect pathway inhibition by the adenosine A2a antagonist SYN115 in Parkinson disease. J Neurosci 2010;30:16284-92
119. Gillespie RJ, Bamford SJ, Botting R, et al. Antagonists of the human A(2A) adenosine receptor. 4. Design, synthesis, and preclinical evaluation of 7-aryltriazolo[4,5-d]pyrimidines. J Med Chem 2009;52:33-47
120. He P, Papapetropoulos S, O'Neill GN, et al. Pharmacokinetic profile of the adenosine A2A receptor antagonist BIIB014 in healthy volunteers. Mov Disord 2010;25(Suppl 2):S298
121. Brooks DJ, Papapetropoulos S, Vandenhende F, et al. An open-label, positron emission tomography study to assess adenosine A2A brain receptor occupancy of vipadenant (BIIB014) at steady-state levels in healthy male volunteers. Clin Neuropharmacol 2010;33:55-60
122. Papapetropoulos S, He P, Zhu Y, et al. Safety and tolerability profile of adeosine A2A receptor antagonist BIIB014 in healthy volunteers: pooled analysis of four phase 1 studies. Mov Disord 2010;25(Suppl 2):S304
123. Papapetropoulos S, Borgohain R, Kellet M, et al. Safety and tolerability profile of the adenosine A2A receptor antagonist BIIB014 in Parkinson's disease: Pooled analysis of two placebo-controlled 8-week studies. Mov Disord 2010;25(Suppl 2):S304
124. Papapetropoulos S, Borgohain R, Kellet M, et al. The adenosine A2A receptor antagonist BIIB014 is effective in improving ON-time in Parkinson's disease (PD) patients with motor fluctuations. Mov Disord 2010;25(Suppl 2):S305
125. Pinna A. Novel investigational adenosine A2A receptor antagonists for Parkinson's disease. Expert Opin Investig Drugs 2009;18:1619-31
126. Rose S, Jackson MJ, Smith LA, et al. The novel adenosine A2a receptor antagonist ST1535 potentiates the effects of a threshold dose of L-DOPA in MPTP treated common marmosets. Eur J Pharmacol 2006;546:82-7 (Pubitemid 44348896)
127. Rose S, Ramsay Croft N, Jenner P. The novel adenosine A2a antagonist ST1535 potentiates the effects of a threshold dose of l-dopa in unilaterally 6-OHDA-lesioned rats. Brain Res 2007;1133:110-14 (Pubitemid 46123239)
128. Pinna A, Pontis S, Borsini F, Morelli M. Adenosine A2A receptor antagonists improve deficits in initiation of movement and sensory motor integration in the unilateral 6-hydroxydopamine rat model of Parkinson's disease. Synapse 2007;61:606-14. (Pubitemid 46934007)