A2A Adenosine Receptor Antagonists and their Potential in Neurological
Disorders

Catia      Lambertucci; Gabriella      Marucci; Daniela      Catarzi; Vittoria      Colotta; Beatrice      Francucci; Andrea      Spinaci; Flavia      Varano; Rosaria      Volpini
doi:10.2174/0929867329666220218094501
Abstract

Endogenous nucleoside adenosine modulates a number of physiological effects through interaction with P1 purinergic receptors. All of them are G protein-coupled receptors, and, to date, four subtypes have been characterized and named A₁, A_2A, A_2B, and A₃. In recent years, adenosine receptors, particularly the A_2A subtype, have become attractive targets for the treatment of several neurodegenerative disorders, known to involve neuroinflammation, like Parkinson’s and Alzheimer’s diseases, multiple sclerosis, and neuropsychiatric conditions. In fact, it has been demonstrated that inhibition of A2A adenosine receptors exerts neuroprotective effects counteracting neuroinflammatory processes and astroglial and microglial activation. The A_2A adenosine receptor antagonist istradefylline, developed by Kyowa Hakko Kirin Inc., was approved in Japan as adjunctive therapy for the treatment of Parkinson’s disease, and very recently, it was also approved by the US Food and Drug Administration. These findings pave the way for new therapeutic opportunities, so, in this review, a summary of the most relevant and promising A_2A adenosine receptor antagonists will be presented along with their preclinical and clinical studies in neuroinflammation related diseases.
Keywords: A_2A adenosine receptor, A_2A adenosine receptor antagonists, neuroinflammation, neuroprotection, Parkinson’s disease, adenosine receptors, xanthine derivatives, non-xanthine derivatives.
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[1] 
Fredholm, B.B.; IJzerman, A.P.; Jacobson, K.A.; Linden, J.; Müller, C.E. International Union of Basic and Clinical Pharmacology. LXXXI. Nomenclature and classification of adenosine receptors--an update. Pharmacol. Rev.,  2011, 63(1), 1-34.
[http://dx.doi.org/10.1124/pr.110.003285] [PMID: 21303899] 
[2] 
Gomes, C.V.; Kaster, M.P.; Tome, A.R.; Agostinho, P.M.; Cunha, R.A. Adenosine receptors and brain diseases: Neuroprotection and neurodegeneration. Biomembranes,  2011, 1808(5), 1380-1399.
[3] 
Fuxe, K.; Marcellino, D.; Borroto-Escuela, D.O.; Guescini, M.; Fernández-Dueñas, V.; Tanganelli, S.; Rivera, A.; Ciruela, F.; Agnati, L.F. Adenosine-dopamine interactions in the pathophysiology and treatment of CNS disorders. CNS Neurosci. Ther.,  2010, 16(3), e18-e42.
[http://dx.doi.org/10.1111/j.1755-5949.2009.00126.x] [PMID: 20345970] 
[4] 
Fredholm, B.B. Purinoceptors in the nervous system. Pharmacol. Toxicol.,  1995, 76(4), 228-239.
[http://dx.doi.org/10.1111/j.1600-0773.1995.tb00135.x] [PMID: 7617551] 
[5] 
Burnstock, G.; Knight, G.E. Cellular distribution and functions of P2 receptor subtypes in different systems. Int. Rev. Cytol.,  2004, 240, 31-304.
[http://dx.doi.org/10.1016/S0074-7696(04)40002-3] [PMID: 15548415] 
[6] 
Cheng, R.K.Y.; Segala, E.; Robertson, N.; Deflorian, F.; Doré, A.S.; Errey, J.C.; Fiez-Vandal, C.; Marshall, F.H.; Cooke, R.M. Structures of human A1 and A2A Adenosine receptors with xanthines reveal determinants of selectivity. Structure,  2017, 25(8), 1275-1285.e4.
[http://dx.doi.org/10.1016/j.str.2017.06.012] [PMID: 28712806] 
[7] 
Effendi, W.I.; Nagano, T.; Kobayashi, K.; Nishimura, Y. Focusing on Adenosine receptors as a potential targeted therapy in human diseases. Cells,  2020, 9(3), E785.
[http://dx.doi.org/10.3390/cells9030785] [PMID: 32213945] 
[8] 
Dunwiddie, T.V.; Masino, S.A. The role and regulation of adenosine in the central nervous system. Annu. Rev. Neurosci.,  2001, 24, 31-55.
[http://dx.doi.org/10.1146/annurev.neuro.24.1.31] [PMID: 11283304] 
[9] 
Fredholm, B.B.; Chen, J.F.; Cunha, R.A.; Svenningsson, P.; Vaugeois, J.M. Adenosine and brain function. Int. Rev. Neurobiol.,  2005, 63, 191-270.
[http://dx.doi.org/10.1016/S0074-7742(05)63007-3] [PMID: 15797469] 
[10] 
Liu, X.; Huang, P.; Wang, J.; Yang, Z.; Huang, S.; Luo, X.; Qi, J.; Shen, X.; Zhong, Y. The effect of A2A receptor antagonist on microglial activation in experimental glaucoma. Invest. Ophthalmol. Vis. Sci.,  2016, 57(3), 776-786.
[http://dx.doi.org/10.1167/iovs.15-18024] [PMID: 26934133] 
[11] 
Colella, M.; Zinni, M.; Pansiot, J.; Cassanello, M.; Mairesse, J.; Ramenghi, L.; Baud, O. Modulation of microglial activation by adenosine A2a receptor in animal models of perinatal brain injury. Front. Neurol.,  2018, 9, 605.
[http://dx.doi.org/10.3389/fneur.2018.00605] [PMID: 30254599] 
[12] 
Dai, S.S.; Zhou, Y.G.; Li, W.; An, J.H.; Li, P.; Yang, N.; Chen, X.Y.; Xiong, R.P.; Liu, P.; Zhao, Y.; Shen, H.Y.; Zhu, P.F.; Chen, J.F. Local glutamate level dictates adenosine A2A receptor regulation of neuroinflammation and traumatic brain injury. J. Neurosci.,  2010, 30(16), 5802-5810.
[http://dx.doi.org/10.1523/JNEUROSCI.0268-10.2010] [PMID: 20410132] 
[13] 
Patraca, I.; Martinez, N.; Busquets, O.; Marti, A.; Pedros, I.; Beas-Zarate, C.; Marin, M.; Ettcheto, M.; Sureda, F.; Auladell, C.; Camins, A.; Folch, J. Anti-inflammatory role of Leptin in glial cells through p38 MAPK pathway inhibition. Pharmacol. Rep.,  2017, 69(3), 409-418.
[http://dx.doi.org/10.1016/j.pharep.2016.12.005] 
[14] 
Mendiola, A.S.; Cardona, A.E. The IL-1β phenomena in neuroinflammatory diseases. J. Neural Transm. (Vienna),  2018, 125(5), 781-795.
[http://dx.doi.org/10.1007/s00702-017-1732-9] [PMID: 28534174] 
[15] 
Taylor, J.M.; Moore, Z.; Minter, M.R.; Crack, P.J. Type-I interferon pathway in neuroinflammation and neurodegeneration: Focus on Alzheimer’s disease. J. Neural Transm. (Vienna),  2018, 125(5), 797-807.
[http://dx.doi.org/10.1007/s00702-017-1745-4] [PMID: 28676934] 
[16] 
Dorothée, G. Neuroinflammation in neurodegeneration: Role in pathophysiology, therapeutic opportunities and clinical perspectives. J. Neural Transm. (Vienna),  2018, 125(5), 749-750.
[http://dx.doi.org/10.1007/s00702-018-1880-6] [PMID: 29623427] 
[17] 
Rekatsina, M.; Paladini, A.; Piroli, A.; Zis, P.; Pergolizzi, J.V.; Varrassi, G. Pathophysiology and therapeutic perspectives of oxidative stress and neurodegenerative diseases: A narrative review. Adv. Ther.,  2020, 37(1), 113-139.
[http://dx.doi.org/10.1007/s12325-019-01148-5] [PMID: 31782132] 
[18] 
Merighi, S.; Poloni, T.E.; Terrazzan, A.; Moretti, E.; Gessi, S.; Ferrari, D. Alzheimer and purinergic signaling: Just a matter of inflammation? Cells,  2021, 10(5), 1267.
[http://dx.doi.org/10.3390/cells10051267] [PMID: 34065393] 
[19] 
Martí, N.A.; Dal Ben, D.; Lambertucci, C.; Spinaci, A.; Volpini, R.; Marques-Morgado, I.; Coelho, J.E.; Lopes, L.V.; Marucci, G.; Buccioni, M. Adenosine receptors as neuroinflammation modulators: Role of A1 agonists and A2A antagonists. Cells,  2020, 9(7), E1739.
[http://dx.doi.org/10.3390/cells9071739] [PMID: 32708189] 
[20] 
Marucci, G.; Ben, D.D.; Lambertucci, C.; Navia, A.M.; Spinaci, A.; Volpini, R.; Buccioni, M. Combined therapy of A1AR agonists and A2AAR antagonists in neuroinflammation. Molecules,  2021, 26(4), 1188.
[http://dx.doi.org/10.3390/molecules26041188] [PMID: 33672225] 
[21] 
Bhalala, U.S.; Koehler, R.C.; Kannan, S. Neuroinflammation and neuroimmune dysregulation after acute hypoxic-ischemic injury of developing brain. Front. Pediatr.,  2015, 2, 144.
[http://dx.doi.org/10.3389/fped.2014.00144] [PMID: 25642419] 
[22] 
Yu, C.; Gupta, J.; Chen, J.F.; Yin, H.H. Genetic deletion of A2A adenosine receptors in the striatum selectively impairs habit formation. J. Neurosci.,  2009, 29(48), 15100-15103.
[http://dx.doi.org/10.1523/JNEUROSCI.4215-09.2009] [PMID: 19955361] 
[23] 
Saura, J.; Angulo, E.; Ejarque, A.; Casadó, V.; Tusell, J.M.; Moratalla, R.; Chen, J.F.; Schwarzschild, M.A.; Lluis, C.; Franco, R.; Serratosa, J. Adenosine A2A receptor stimulation potentiates nitric oxide release by activated microglia. J. Neurochem.,  2005, 95(4), 919-929.
[http://dx.doi.org/10.1111/j.1471-4159.2005.03395.x] [PMID: 16092928] 
[24] 
Minghetti, L.; Greco, A.; Potenza, R.L.; Pezzola, A.; Blum, D.; Bantubungi, K.; Popoli, P. Effects of the adenosine A2A receptor antagonist SCH 58621 on cyclooxygenase-2 expression, glial activation, and brain-derived neurotrophic factor availability in a rat model of striatal neurodegeneration. J. Neuropathol. Exp. Neurol.,  2007, 66(5), 363-371.
[http://dx.doi.org/10.1097/nen.0b013e3180517477] [PMID: 17483693] 
[25] 
Melani, A.; Cipriani, S.; Vannucchi, M.G.; Nosi, D.; Donati, C.; Bruni, P.; Giovannini, M.G.; Pedata, F. Selective adenosine A2a receptor antagonism reduces JNK activation in oligodendrocytes after cerebral ischaemia. Brain,  2009, 132(Pt 6), 1480-1495.
[http://dx.doi.org/10.1093/brain/awp076] [PMID: 19359287] 
[26] 
Kanda, T.; Uchida, S. Clinical/pharmacological aspect of adenosine A2A receptor antagonist for dyskinesia. Int. Rev. Neurobiol.,  2014, 119, 127-150.
[http://dx.doi.org/10.1016/B978-0-12-801022-8.00006-4] [PMID: 25175964] 
[27] 
Atack, J.R.; Shook, B.C.; Rassnick, S.; Jackson, P.F.; Rhodes, K.; Drinkenburg, W.H.; Ahnaou, A.; Te Riele, P.; Langlois, X.; Hrupka, B.; De Haes, P.; Hendrickx, H.; Aerts, N.; Hens, K.; Wellens, A.; Vermeire, J.; Megens, A.A. JNJ-40255293, a novel adenosine A2A/A1 antagonist with efficacy in preclinical models of Parkinson’s disease. ACS Chem. Neurosci.,  2014, 5(10), 1005-1019.
[http://dx.doi.org/10.1021/cn5001606] [PMID: 25203719] 
[28] 
Santiago, A.R.; Baptista, F.I.; Santos, P.F.; Cristóvão, G.; Ambrósio, A.F.; Cunha, R.A.; Gomes, C.A. Role of microglia adenosine A(2A) receptors in retinal and brain neurodegenerative diseases. Mediators Inflamm.,  2014, 2014, 465694.
[http://dx.doi.org/10.1155/2014/465694] [PMID: 25132733] 
[29] 
Gomes, C.; Ferreira, R.; George, J.; Sanches, R.; Rodrigues, D.I.; Gonçalves, N.; Cunha, R.A. Activation of microglial cells triggers a release of brain-derived neurotrophic factor (BDNF) inducing their proliferation in an adenosine A2A receptor-dependent manner: A2A receptor blockade prevents BDNF release and proliferation of microglia. J. Neuroinflammation,  2013, 10, 16.
[http://dx.doi.org/10.1186/1742-2094-10-16] [PMID: 23363775] 
[30] 
Sheth, S.; Brito, R.; Mukherjea, D.; Rybak, L.P.; Ramkumar, V. Adenosine receptors: Expression, function and regulation. Int. J. Mol. Sci.,  2014, 15(2), 2024-2052.
[http://dx.doi.org/10.3390/ijms15022024] [PMID: 24477263] 
[31] 
Elson, G.; Eisenberg, M.; Garg, C.; Outram, S.; Ferrante, C.J.; Hasko, G.; Leibovich, S.J. Induction of murine adenosine A(2A) receptor expression by LPS: Analysis of the 5′ upstream promoter. Genes Immun.,  2013, 14(3), 147-153.
[http://dx.doi.org/10.1038/gene.2012.60] [PMID: 23328845] 
[32] 
Laurent, C.; Burnouf, S.; Ferry, B.; Batalha, V.L.; Coelho, J.E.; Baqi, Y.; Malik, E.; Marciniak, E.; Parrot, S.; Van der Jeugd, A.; Faivre, E.; Flaten, V.; Ledent, C.; D’Hooge, R.; Sergeant, N.; Hamdane, M.; Humez, S.; Müller, C.E.; Lopes, L.V.; Buée, L.; Blum, D. A2A adenosine receptor deletion is protective in a mouse model of Tauopathy. Mol. Psychiatry,  2016, 21(1), 149-149.
[http://dx.doi.org/10.1038/mp.2015.115] [PMID: 26216297] 
[33] 
Ferreira, D.G.; Batalha, V.L.; Vicente, M.H.; Coelho, J.E.; Gomes, R.; Gonçalves, F.Q.; Real, J.I.; Rino, J.; Albino-Teixeira, A.; Cunha, R.A.; Outeiro, T.F.; Lopes, L.V.; Adenosine, A. Adenosine A2A receptors modulate α-synuclein aggregation and toxicity. Cereb. Cortex,  2017, 27(1), 718-730.
[PMID: 26534909] 
[34] 
de Souza, M.F.; Bispo, J.M.M.; Leal, P.C.; de Gois, A.M.; Dos Santos, J.R. Commentary: Adenosine A2A receptor blockade prevents rotenone-induced motor impairment in a rat model of Parkinsonism. Front. Behav. Neurosci.,  2017, 11, 93.
[http://dx.doi.org/10.3389/fnbeh.2017.00093] [PMID: 28579949] 
[35] 
Ferré, S.; Ciruela, F. Functional and Neuroprotective Role of striatal Adenosine A2A receptor heterotetramers. J. Caffeine Adenosine Res.,  2019, 9(3), 89-97.
[http://dx.doi.org/10.1089/caff.2019.0008] [PMID: 31559390] 
[36] 
Jamwal, S.; Kumar, P. Insight into the emerging role of striatal neurotransmitters in the pathophysiology of Parkinson’s disease and Huntington’s disease: A review. Curr. Neuropharmacol.,  2019, 17(2), 165-175.
[http://dx.doi.org/10.2174/1570159X16666180302115032] [PMID: 29512464] 
[37] 
Prasad, K.; de Vries, E.F.J.; Elsinga, P.H.; Dierckx, R.A.J.O.; van Waarde, A. Allosteric interactions between Adenosine A2A and Dopamine D2 receptors in heteromeric complexes: Biochemical and pharmacological characteristics, and opportunities for PET imaging. Int. J. Mol. Sci.,  2021, 22(4), 1719.
[http://dx.doi.org/10.3390/ijms22041719] [PMID: 33572077] 
[38] 
Pourcher, E.; Huot, P. Adenosine 2A receptor antagonists for the treatment of motor symptoms in Parkinson’s disease. Mov. Disord. Clin. Pract. (Hoboken),  2015, 2(4), 331-340.
[http://dx.doi.org/10.1002/mdc3.12187] [PMID: 30363540] 
[39] 
Fredholm, B.B.; Bättig, K.; Holmén, J.; Nehlig, A.; Zvartau, E.E. Actions of caffeine in the brain with special reference to factors that contribute to its widespread use. Pharmacol. Rev.,  1999, 51(1), 83-133.
[PMID: 10049999] 
[40] 
Costenla, A.R.; Cunha, R.A.; de Mendonça, A. Caffeine, adenosine receptors, and synaptic plasticity. J. Alzheimers Dis.,  2010, 20(Suppl. 1), S25-S34.
[http://dx.doi.org/10.3233/JAD-2010-091384] [PMID: 20182030] 
[41] 
Ritchie, K.; Carrière, I.; de Mendonca, A.; Portet, F.; Dartigues, J.F.; Rouaud, O.; Barberger-Gateau, P.; Ancelin, M.L. The neuroprotective effects of caffeine: A prospective population study (the Three City Study). Neurology,  2007, 69(6), 536-545.
[http://dx.doi.org/10.1212/01.wnl.0000266670.35219.0c] [PMID: 17679672] 
[42] 
Stockwell, J.; Jakova, E.; Cayabyab, F.S. Adenosine A1 and A2A receptors in the brain: Current research and their role in neurodegeneration. Molecules,  2017, 22(4), E676.
[http://dx.doi.org/10.3390/molecules22040676] [PMID: 28441750] 
[43] 
James, J.E. Critical review of dietary caffeine and blood pressure: A relationship that should be taken more seriously. Psychosom. Med.,  2004, 66(1), 63-71.
[http://dx.doi.org/10.1097/10.PSY.0000107884.78247.F9] [PMID: 14747639] 
[44] 
Janitschke, D.; Lauer, A.A.; Bachmann, C.M.; Grimm, H.S.; Hartmann, T.; Grimm, M.O.W. Methylxanthines and neurodegenerative diseases: An update. Nutrients,  2021, 13(3), 803.
[http://dx.doi.org/10.3390/nu13030803] [PMID: 33671099] 
[45] 
Schepici, G.; Silvestro, S.; Bramanti, P.; Mazzon, E. Caffeine: An overview of its beneficial effects in experimental models and clinical trials of Parkinson’s disease. Int. J. Mol. Sci.,  2020, 21(13), E4766.
[http://dx.doi.org/10.3390/ijms21134766] [PMID: 32635541] 
[46] 
Maia, L.; de Mendonça, A. Does caffeine intake protect from Alzheimer’s disease? Eur. J. Neurol.,  2002, 9(4), 377-382.
[http://dx.doi.org/10.1046/j.1468-1331.2002.00421.x] [PMID: 12099922] 
[47] 
Oñatibia-Astibia, A.; Franco, R.; Martínez-Pinilla, E. Health benefits of methylxanthines in neurodegenerative diseases. Mol. Nutr. Food Res., 2017.
[http://dx.doi.org/10.1002/mnfr.201600670] [PMID: 28074613] 
[48] 
Iranpour, S.; Saadati, H.M.; Koohi, F.; Sabour, S. Association between caffeine intake and cognitive function in adults; effect modification by sex: Data from National Health and Nutrition Examination Survey (NHANES) 2013-2014. Clin. Nutr.,  2020, 39(7), 2158-2168.
[http://dx.doi.org/10.1016/j.clnu.2019.09.003] [PMID: 31582197] 
[49] 
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.
[http://dx.doi.org/10.1021/jm00062a005] [PMID: 8496902] 
[50] 
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.
[http://dx.doi.org/10.1074/jbc.M206830200] [PMID: 12130655] 
[51] 
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.
[http://dx.doi.org/10.1016/S0968-0896(02)00648-X] [PMID: 12628657] 
[52] 
van den Berg, D.; Zoellner, K.R.; Ogunrombi, M.O.; Malan, S.F.; Terre’Blanche, G.; Castagnoli, N., Jr; Bergh, J.J.; Petzer, J.P. Inhibition of monoamine oxidase B by selected benzimidazole and caffeine analogues. Bioorg. Med. Chem.,  2007, 15(11), 3692-3702.
[http://dx.doi.org/10.1016/j.bmc.2007.03.046] [PMID: 17416530] 
[53] 
Sauer, R.; Maurinsh, J.; Reith, U.; Fülle, F.; Klotz, K.N.; Müller, C.E. Water-soluble phosphate prodrugs of 1-propargyl-8-styrylxanthine derivatives, A(2A)-selective adenosine receptor antagonists. J. Med. Chem.,  2000, 43(3), 440-448.
[http://dx.doi.org/10.1021/jm9911480] [PMID: 10669571] 
[54] 
Faivre, E.; Coelho, J.E.; Zornbach, K.; Malik, E.; Baqi, Y.; Schneider, M.; Cellai, L.; Carvalho, K.; Sebda, S.; Figeac, M.; Eddarkaoui, S.; Caillierez, R.; Chern, Y.; Heneka, M.; Sergeant, N.; Müller, C.E.; Halle, A.; Buée, L.; Lopes, L.V.; Blum, D. Beneficial effect of a selective Adenosine A2A receptor antagonist in the APPswe/PS1dE9 mouse model of Alzheimer’s Disease. Front. Mol. Neurosci.,  2018, 11, 235.
[http://dx.doi.org/10.3389/fnmol.2018.00235] [PMID: 30050407] 
[55] 
Cristalli, G.; Lambertucci, C.; Marucci, G.; Volpini, R.; Dal Ben, D. A2A adenosine receptor and its modulators: Overview on a druggable GPCR and on structure-activity relationship analysis and binding requirements of agonists and antagonists. Curr. Pharm. Des.,  2008, 14(15), 1525-1552.
[http://dx.doi.org/10.2174/138161208784480081] [PMID: 18537675] 
[56] 
Cristalli, G.; Müller, C.E.; Volpini, R. Recent developments in adenosine A2A receptor ligands. Handb. Exp. Pharmacol.,  2009, (193), 59-98.
[http://dx.doi.org/10.1007/978-3-540-89615-9_3] [PMID: 19639279] 
[57] 
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, 7, 2349-2352.
[http://dx.doi.org/10.1016/S0960-894X(97)00440-X] 
[58] 
Pierri, M.; Vaudano, E.; Sager, T.; Englund, U. KW-6002 protects from MPTP induced dopaminergic toxicity in the mouse. Neuropharmacology,  2005, 48(4), 517-524.
[http://dx.doi.org/10.1016/j.neuropharm.2004.11.009] [PMID: 15755479] 
[59] 
Chen, J.F.; Cunha, R.A. The belated US FDA approval of the adenosine A2A receptor antagonist istradefylline for treatment of Parkinson’s disease. Purinergic Signal.,  2020, 16(2), 167-174.
[http://dx.doi.org/10.1007/s11302-020-09694-2] [PMID: 32236790] 
[60] 
Kim, S.A.; Marshall, M.A.; Melman, N.; Kim, H.S.; Müller, C.E.; Linden, J.; Jacobson, K.A. Structure-activity relationships at human and rat A2B adenosine receptors of xanthine derivatives substituted at the 1-, 3-, 7-, and 8-positions. J. Med. Chem.,  2002, 45(11), 2131-2138.
[http://dx.doi.org/10.1021/jm0104318] [PMID: 12014951] 
[61] 
Cacciari, B.; Spalluto, G.; Federico, S. A2A Adenosine receptor antagonists as therapeutic candidates: Are they still an interesting challenge? Mini Rev. Med. Chem.,  2018, 18(14), 1168-1174.
[http://dx.doi.org/10.2174/1389557518666180423113051] [PMID: 29692248] 
[62] 
Jacobson, K.A.; IJzerman, A.P.; Linden, J. 1,3-dialkylxanthine derivatives having high potency as antagonists at human A2B adenosine receptors. Drug Dev. Res.,  1999, 47, 45-53.
[http://dx.doi.org/10.1002/(SICI)1098-2299(199905)47:1<45::AID-DDR6>3.0.CO;2-U] 
[63] 
Klotz, K.N.; Hessling, J.; Hegler, J.; Owman, C.; Kull, B.; Fredholm, B.B.; Lohse, M.J. Comparative pharmacology of human adenosine receptor subtypes - characterization of stably transfected receptors in CHO cells. Naunyn Schmiedebergs Arch. Pharmacol.,  1998, 357(1), 1-9.
[http://dx.doi.org/10.1007/PL00005131] [PMID: 9459566] 
[64] 
Knutsen, L.J.; Weiss, S.M. KW-6002 (Kyowa Hakko Kogyo). Curr. Opin. Investig. Drugs,  2001, 2(5), 668-673.
[PMID: 11569945] 
[65] 
Weiss, S.M.; Benwell, K.; Cliffe, I.A.; Gillespie, R.J.; Knight, A.R.; Lerpiniere, J.; Misra, A.; Pratt, R.M.; Revell, D.; Upton, R.; Dourish, C.T. Discovery of nonxanthine adenosine A2A receptor antagonists for the treatment of Parkinson’s disease. Neurology,  2003, 61(11)(Suppl. 6), S101-S106.
[http://dx.doi.org/10.1212/01.WNL.0000095581.20961.7D] [PMID: 14663021] 
[66] 
Drabczyńska, A.; Yuzlenko, O.; Köse, M.; Paskaleva, M.; Schiedel, A.C.; Karolak-Wojciechowska, J.; Handzlik, J.; Karcz, T.; Kuder, K.; Müller, C.E.; Kieć-Kononowicz, K. Synthesis and biological activity of tricyclic cycloalkylimidazo-, pyrimido- and diazepinopurinediones. Eur. J. Med. Chem.,  2011, 46(9), 3590-3607.
[http://dx.doi.org/10.1016/j.ejmech.2011.05.023] [PMID: 21664729] 
[67] 
Francis, J.E.; Cash, W.D.; Psychoyos, S.; Ghai, G.; Wenk, P.; Friedmann, R.C.; Atkins, C.; Warren, V.; Furness, P.; Hyun, J.L. Structure-activity profile of a series of novel triazoloquinazoline adenosine antagonists. J. Med. Chem.,  1988, 31(5), 1014-1020.
[http://dx.doi.org/10.1021/jm00400a022] [PMID: 3361572] 
[68] 
Sarges, R.; Howard, H.R.; Browne, R.G.; Lebel, L.A.; Seymour, P.A.; Koe, B.K. 4-Amino[1,2,4]triazolo[4,3-a]quinoxalines. A novel class of potent adenosine receptor antagonists and potential rapid-onset antidepressants. J. Med. Chem.,  1990, 33(8), 2240-2254.
[http://dx.doi.org/10.1021/jm00170a031] [PMID: 2374150] 
[69] 
Baraldi, P.G.; Cacciari, B.; Romagnoli, R.; Spalluto, G.; Moro, S.; Klotz, K.N.; Leung, E.; Varani, K.; Gessi, S.; Merighi, S.; Borea, P.A. Pyrazolo[4,3-e]1,2,4-triazolo[1,5-c]pyrimidine derivatives as highly potent and selective human A(3) adenosine receptor antagonists: Influence of the chain at the N(8) pyrazole nitrogen. J. Med. Chem.,  2000, 43(25), 4768-4780.
[http://dx.doi.org/10.1021/jm001047y] [PMID: 11123985] 
[70] 
Gatta, F.; Del Giudice, M.R.; Borioni, A.; Borea, P.A.; Dionisotti, S.; Ongini, E. Synthesis of imidazo[1,2-c]pyrazolo[4,3-e]pyrimidines, pyrazolo[4,3-e]1,2,4-triazolo[1,5-c]pyrimidines and 1,2,4-triazolo[5,1-i]purines: New potent adenosine A2 receptor antagonists. Eur. J. Med. Chem.,  1993, 569-577.
[http://dx.doi.org/10.1016/0223-5234(93)90087-U] 
[71] 
Baraldi, P.G.; Cacciari, B.; Spalluto, G.; Bergonzoni, M.; Dionisotti, S.; Ongini, E.; Varani, K.; Borea, P.A. Design, synthesis, and biological evaluation of a second generation of pyrazolo[4,3-e]-1,2,4-triazolo[1,5-c]pyrimidines as potent and selective A2A adenosine receptor antagonists. J. Med. Chem.,  1998, 41(12), 2126-2133.
[http://dx.doi.org/10.1021/jm9708689] [PMID: 9622554] 
[72] 
Zocchi, C.; Ongini, E.; Conti, A.; Monopoli, A.; Negretti, A.; Baraldi, P.G.; Dionisotti, S. The non-xanthine heterocyclic compound SCH 58261 is a new potent and selective A2a adenosine receptor antagonist. J. Pharmacol. Exp. Ther.,  1996, 276(2), 398-404.
[PMID: 8632302] 
[73] 
Baraldi, P.G.; Cacciari, B.; Spalluto, G.; Pineda de las Infantas y Villatoro, M.J.; Zocchi, C.; Dionisotti, S.; Ongini, E. Pyrazolo[4,3-e]-1,2,4-triazolo[1,5-c]pyrimidine derivatives: Potent and selective A(2A) adenosine antagonists. J. Med. Chem.,  1996, 39(5), 1164-1171.
[http://dx.doi.org/10.1021/jm950746l] [PMID: 8676354] 
[74] 
Todde, S.; Moresco, R.M.; Simonelli, P.; Baraldi, P.G.; Cacciari, B.; Spalluto, G.; Varani, K.; Monopoli, A.; Matarrese, M.; Carpinelli, A.; Magni, F.; Kienle, M.G.; Fazio, F. Design, radiosynthesis, and biodistribution of a new potent and selective ligand for in vivo imaging of the adenosine A(2A) receptor system using positron emission tomography. J. Med. Chem.,  2000, 43(23), 4359-4362.
[http://dx.doi.org/10.1021/jm0009843] [PMID: 11087559] 
[75] 
Kecskés, M.; Kumar, T.S.; Yoo, L.; Gao, Z.G.; Jacobson, K.A. Novel Alexa Fluor-488 labeled antagonist of the A(2A) adenosine receptor: Application to a fluorescence polarization-based receptor binding assay. Biochem. Pharmacol.,  2010, 80(4), 506-511.
[http://dx.doi.org/10.1016/j.bcp.2010.04.027] [PMID: 20438717] 
[76] 
Baraldi, P.G.; Cacciari, B.; Romagnoli, R.; Spalluto, G.; Monopoli, A.; Ongini, E.; Varani, K.; Borea, P.A. 7-Substituted 5-amino-2-(2-furyl)pyrazolo[4,3-e]-1,2,4-triazolo[1,5-c]pyrimidines as A2A adenosine receptor antagonists: A study on the importance of modifications at the side chain on the activity and solubility. J. Med. Chem.,  2002, 45(1), 115-126.
[http://dx.doi.org/10.1021/jm010924c] [PMID: 11754583] 
[77] 
Baraldi, P.G.; Tabrizi, M.A.; Gessi, S.; Borea, P.A. Adenosine receptor antagonists: Translating medicinal chemistry and pharmacology into clinical utility. Chem. Rev.,  2008, 108(1), 238-263.
[http://dx.doi.org/10.1021/cr0682195] [PMID: 18181659] 
[78] 
Neustadt, B.R.; Hao, J.; Lindo, N.; Greenlee, W.J.; Stamford, A.W.; Tulshian, D.; Ongini, E.; Hunter, J.; Monopoli, A.; Bertorelli, R.; Foster, C.; Arik, L.; Lachowicz, J.; Ng, K.; Feng, K.I. 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(5), 1376-1380.
[http://dx.doi.org/10.1016/j.bmcl.2006.11.083] [PMID: 17236762] 
[79] 
Cacciari, B.; Pastorin, G.; Spalluto, G. Medicinal chemistry of A2A adenosine receptor antagonists. Curr. Top. Med. Chem.,  2003, 3(4), 403-411.
[http://dx.doi.org/10.2174/1568026033392183] [PMID: 12570758] 
[80] 
Müller, C.E.; Jacobson, K.A. Recent developments in adenosine receptor ligands and their potential as novel drugs. Biochim. Biophys. Acta,  2011, 1808(5), 1290-1308.
[http://dx.doi.org/10.1016/j.bbamem.2010.12.017] [PMID: 21185259] 
[81] 
Ji, X.D.; Jacobson, K.A. Use of the triazolotriazine [3H]ZM 241385 as a radioligand at recombinant human A2B adenosine receptors. Drug Des. Discov.,  1999, 16(3), 217-226.
[PMID: 10624567] 
[82] 
Gillespie, R.J.; Bamford, S.J.; Botting, R.; Comer, M.; Denny, S.; Gaur, S.; Griffin, M.; Jordan, A.M.; Knight, A.R.; Lerpiniere, J.; Leonardi, S.; Lightowler, S.; McAteer, S.; Merrett, A.; Misra, A.; Padfield, A.; Reece, M.; Saadi, M.; Selwood, D.L.; Stratton, G.C.; Surry, D.; Todd, R.; Tong, X.; Ruston, V.; Upton, R.; Weiss, S.M. 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(1), 33-47.
[http://dx.doi.org/10.1021/jm800961g] [PMID: 19072055] 
[83] 
Willingham, S.B.; Ho, P.Y.; Hotson, A.; Hill, C.; Piccione, E.C.; Hsieh, J.; Liu, L.; Buggy, J.J.; McCaffery, I.; Miller, R.A. A2AR antagonism with CPI-444 induces antitumor responses and augments efficacy to anti-PD-(L)1 and anti-CTLA-4 in preclinical models. Cancer Immunol. Res.,  2018, 6(10), 1136-1149.
[http://dx.doi.org/10.1158/2326-6066.CIR-18-0056] [PMID: 30131376] 
[84] 
Falsini, M.; Catarzi, D.; Varano, F.; Ceni, C.; Dal Ben, D.; Marucci, G.; Buccioni, M.; Volpini, R.; Di Cesare Mannelli, L.; Lucarini, E.; Ghelardini, C.; Bartolucci, G.; Menicatti, M.; Colotta, V. Antioxidant-Conjugated 1,2,4-Triazolo[4,3-a]pyrazin-3-one Derivatives: Highly potent and selective human A2A Adenosine receptor antagonists possessing protective efficacy in neuropathic pain. J. Med. Chem.,  2019, 62(18), 8511-8531.
[http://dx.doi.org/10.1021/acs.jmedchem.9b00778] [PMID: 31453698] 
[85] 
Minetti, P.; Tinti, M.O.; Carminati, P.; Castorina, M.; Di Cesare, M.A.; Di Serio, S.; Gallo, G.; Ghirardi, O.; Giorgi, F.; Giorgi, L.; Piersanti, G.; Bartoccini, F.; Tarzia, G. 2-n-Butyl-9-methyl-8-[1,2,3]triazol-2-yl-9H-purin-6-ylamine and analogues as A2A adenosine receptor antagonists. Design, synthesis, and pharmacological characterization. J. Med. Chem.,  2005, 48(22), 6887-6896.
[http://dx.doi.org/10.1021/jm058018d] [PMID: 16250647] 
[86] 
Piersanti, G.; Bartoccini, F.; Lucarini, S.; Cabri, W.; Stasi, M.A.; Riccioni, T.; Borsini, F.; Tarzia, G.; Minetti, P. Synthesis and biological evaluation of metabolites of 2-n-butyl-9-methyl-8-[1,2,3]triazol-2-yl-9H-purin-6-ylamine (ST1535), a potent antagonist of the A2A adenosine receptor for the treatment of Parkinson’s disease. J. Med. Chem.,  2013, 56(13), 5456-5463.
[http://dx.doi.org/10.1021/jm400491x] [PMID: 23789814] 
[87] 
Camaioni, E.; Costanzi, S.; Vittori, S.; Volpini, R.; Klotz, K.N.; Cristalli, G. New substituted 9-alkylpurines as adenosine receptor ligands. Bioorg. Med. Chem.,  1998, 6(5), 523-533.
[http://dx.doi.org/10.1016/S0968-0896(98)00007-8] [PMID: 9629466] 
[88] 
Volpini, R.; Dal Ben, D.; Lambertucci, C.; Marucci, G.; Mishra, R.C.; Ramadori, A.T.; Klotz, K.N.; Trincavelli, M.L.; Martini, C.; Cristalli, G. Adenosine A2A receptor antagonists: New 8-substituted 9-ethyladenines as tools for in vivo rat models of Parkinson’s disease. ChemMedChem,  2009, 4(6), 1010-1019.
[http://dx.doi.org/10.1002/cmdc.200800434] [PMID: 19343763] 
[89] 
Klotz, K.N.; Kachler, S.; Lambertucci, C.; Vittori, S.; Volpini, R.; Cristalli, G. 9-Ethyladenine derivatives as adenosine receptor antagonists: 2- and 8-substitution results in distinct selectivities. Naunyn Schmiedebergs Arch. Pharmacol.,  2003, 367(6), 629-634.
[http://dx.doi.org/10.1007/s00210-003-0749-9] [PMID: 12734636] 
[90] 
Betti, M.; Catarzi, D.; Varano, F.; Falsini, M.; Varani, K.; Vincenzi, F.; Pasquini, S.; di Cesare Mannelli, L.; Ghelardini, C.; Lucarini, E.; Dal Ben, D.; Spinaci, A.; Bartolucci, G.; Menicatti, M.; Colotta, V. Modifications on the Amino-3,5-dicyanopyridine core to obtain multifaceted adenosine receptor ligands with antineuropathic activity. J. Med. Chem.,  2019, 62(15), 6894-6912.
[http://dx.doi.org/10.1021/acs.jmedchem.9b00106] [PMID: 31306001] 
[91] 
Mihara, T.; Mihara, K.; Yarimizu, J.; Mitani, Y.; Matsuda, R.; Yamamoto, H.; Aoki, S.; Akahane, A.; Iwashita, A.; Matsuoka, N. Pharmacological characterization of a novel, potent adenosine A1 and A2A receptor dual antagonist, 5-[5-amino-3-(4-fluorophenyl)pyrazin-2-yl]-1-isopropylpyridine-2(1H)-one (ASP5854), in models of Parkinson’s disease and cognition. J. Pharmacol. Exp. Ther.,  2007, 323(2), 708-719.
[http://dx.doi.org/10.1124/jpet.107.121962] [PMID: 17684118] 
[92] 
Jenner, P.; Mori, A.; Kanda, T. Can adenosine A2A receptor antagonists be used to treat cognitive impairment, depression or excessive sleepiness in Parkinson’s disease? Parkinsonism Relat. Disord.,  2020, 80(Suppl. 1), S28-S36.
[http://dx.doi.org/10.1016/j.parkreldis.2020.09.022] [PMID: 33349577] 
[93] 
Kotańska, M.; Dziubina, A.; Szafarz, M.; Mika, K.; Reguła, K.; Bednarski, M.; Zygmunt, M.; Drabczyńska, A.; Sapa, J.; Kieć-Kononowicz, K. KD-64-A new selective A2A adenosine receptor antagonist has anti-inflammatory activity but contrary to the non-selective antagonist-Caffeine does not reduce diet-induced obesity in mice. PLoS One,  2020, 15(6), e0229806.
[http://dx.doi.org/10.1371/journal.pone.0229806] [PMID: 32555600] 
[94] 
Hutchison, A.J.; Webb, R.L.; Oei, H.H.; Ghai, G.R.; Zimmerman, M.B.; Williams, M. CGS 21680C, an A2 selective adenosine receptor agonist with preferential hypotensive activity. J. Pharmacol. Exp. Ther.,  1989, 251(1), 47-55.
[PMID: 2795469] 
[95] 
Rebola, N.; Simões, A.P.; Canas, P.M.; Tomé, A.R.; Andrade, G.M.; Barry, C.E.; Agostinho, P.M.; Lynch, M.A.; Cunha, R.A. Adenosine A2A receptors control neuroinflammation and consequent hippocampal neuronal dysfunction. J. Neurochem.,  2011, 117(1), 100-111.
[http://dx.doi.org/10.1111/j.1471-4159.2011.07178.x] [PMID: 21235574] 
[96] 
Mohamed, R.A.; Agha, A.M.; Abdel-Rahman, A.A.; Nassar, N.N. Role of adenosine A2A receptor in cerebral ischemia reperfusion injury: Signaling to phosphorylated extracellular signal-regulated protein kinase (pERK1/2). Neuroscience,  2016, 314, 145-159.
[http://dx.doi.org/10.1016/j.neuroscience.2015.11.059] [PMID: 26642806] 
[97] 
Armentero, M.T.; Pinna, A.; Ferré, S.; Lanciego, J.L.; Müller, C.E.; Franco, R. Past, present and future of A(2A) adenosine receptor antagonists in the therapy of Parkinson’s disease. Pharmacol. Ther.,  2011, 132(3), 280-299.
[http://dx.doi.org/10.1016/j.pharmthera.2011.07.004] [PMID: 21810444] 
[98] 
Salamone, J.D. Preladenant, a novel adenosine A(2A) receptor antagonist for the potential treatment of parkinsonism and other disorders. IDrugs,  2010, 13(10), 723-731.
[PMID: 20878595] 
[99] 
Stocchi, F.; Rascol, O.; Hauser, R.A.; Huyck, S.; Tzontcheva, A.; Capece, R.; Ho, T.W.; Sklar, P.; Lines, C.; Michelson, D.; Hewitt, D.J. Randomized trial of preladenant, given as monotherapy, in patients with early Parkinson disease. Neurology,  2017, 88(23), 2198-2206.
[http://dx.doi.org/10.1212/WNL.0000000000004003] [PMID: 28490648] 
[100] 
Pinna, A.; Costa, G.; Serra, M.; Contu, L.; Morelli, M. Neuroinflammation and L-dopa-induced abnormal involuntary movements in 6-hydroxydopamine-lesioned rat model of Parkinson’s disease are counteracted by combined administration of a 5-HT1A/1B receptor agonist and A2A receptor antagonist. Neuropharmacology,  2021, 196, 108693.
[http://dx.doi.org/10.1016/j.neuropharm.2021.108693] [PMID: 34229013] 
[101] 
Byeon, J.J.; Park, M.H.; Shin, S.H.; Park, Y.; Lee, B.I.; Choi, J.M.; Kim, N.; Park, S.J.; Park, M.J.; Lim, J.H.; Na, Y.G.; Shin, Y.G. In vitro, in silico, and in vivo assessments of pharmacokinetic properties of ZM241385. Molecules,  2020, 25(5), E1106.
[http://dx.doi.org/10.3390/molecules25051106] [PMID: 32131453] 
[102] 
Li, X.; Kang, H.; Liu, X.; Liu, Z.; Shu, K.; Chen, X.; Zhu, S. Effect of adenosine A2A receptor antagonist ZM241385 on amygdala-kindled seizures and progression of amygdala kindling. J. Huazhong Univ. Sci. Technolog. Med. Sci.,  2012, 32(2), 257-264.
[http://dx.doi.org/10.1007/s11596-012-0046-2] [PMID: 22528231] 
[103] 
Jaakola, V.P.; Griffith, M.T.; Hanson, M.A.; Cherezov, V.; Chien, E.Y.; Lane, J.R.; Ijzerman, A.P.; Stevens, R.C. The 2.6 angstrom crystal structure of a human A2A adenosine receptor bound to an antagonist. Science,  2008, 322(5905), 1211-1217.
[http://dx.doi.org/10.1126/science.1164772] [PMID: 18832607] 
[104] 
Carpenter, B.; Lebon, G. Human adenosine A2A receptor: Molecular mechanism of ligand binding and activation. Front. Pharmacol.,  2017, 8, 898.
[http://dx.doi.org/10.3389/fphar.2017.00898] [PMID: 29311917] 
[105] 
U.S. National Library of Medicine. Safety and tolerability of tozadenant as adjunctive therapy in levodopa-treated patients with Parkinson's Disease. 2019.  Available from: https://clinicaltrials.gov/ct2/show/NCT03051607
[106] 
U.S. National Library of Medicine. An fMRI study of SYN115 in cocaine dependent subjects. 2019.  Available from: https://clinicaltrials.gov/ct2/show/NCT00783276
[107] 
Pinna, A. Adenosine A2A receptor antagonists in Parkinson’s disease: Progress in clinical trials from the newly approved istradefylline to drugs in early development and those already discontinued. CNS Drugs,  2014, 28(5), 455-474.
[http://dx.doi.org/10.1007/s40263-014-0161-7] [PMID: 24687255] 
[108] 
U.S. National Library of Medicine. Phase 1/1b study to evaluate the safety and tolerability of ciforadenant alone and in combination with atezolizumab in advanced cancers. 2021.  Available from: https://clinicaltrials.gov/ct2/show/NCT02655822
[109] 
Vernalis. Promising results of phase Ib/II proof-of-concept study in Attention Deficit Hyperactivity Disorder (ADHD) with V81444.   Available from: https://www.vernalis.com/promising-results-of-phase-ib-ii-proof-of-concept-study-in-attention-deficit-hyperactivity-disorder-adhd-with-v81444/
[110] 
Falsini, M.; Catarzi, D.; Varano, F.; Dal Ben, D.; Marucci, G.; Buccioni, M.; Volpini, R.; Di Cesare Mannelli, L.; Ghelardini, C.; Colotta, V. Novel 8-amino-1,2,4-triazolo[4,3-a]pyrazin-3-one derivatives as potent human adenosine A1 and A2A receptor antagonists. Evaluation of their protective effect against β-amyloid-induced neurotoxicity in SH-SY5Y cells. Bioorg. Chem.,  2019, 87, 380-394.
[http://dx.doi.org/10.1016/j.bioorg.2019.03.046] [PMID: 30913470] 
[111] 
Ukena, D.; Padgett, W.L.; Hong, O.; Daly, J.W.; Daly, D.T.; Olsson, R.A. N6-substituted 9-methyladenines: A new class of adenosine receptor antagonists. FEBS Lett.,  1987, 215(2), 203-208.
[http://dx.doi.org/10.1016/0014-5793(87)80146-1] [PMID: 3582647] 
[112] 
Stasi, M.A.; Minetti, P.; Lombardo, K.; Riccioni, T.; Caprioli, A.; Vertechy, M.; Di Serio, S.; Pace, S.; Borsini, F. Animal models of Parkinson׳s disease: Effects of two adenosine A2A receptor antagonists ST4206 and ST3932, metabolites of 2-n-Butyl-9-methyl-8-[1,2,3]triazol-2-yl-9H-purin-6-ylamine (ST1535). Eur. J. Pharmacol.,  2015, 761, 353-361.
[http://dx.doi.org/10.1016/j.ejphar.2015.03.070] [PMID: 25936513] 
[113] 
Frau, L.; Borsini, F.; Wardas, J.; Khairnar, A.S.; Schintu, N.; Morelli, M. Neuroprotective and anti-inflammatory effects of the adenosine A(2A) receptor antagonist ST1535 in a MPTP mouse model of Parkinson’s disease. Synapse,  2011, 65(3), 181-188.
[http://dx.doi.org/10.1002/syn.20833] [PMID: 20665698] 
[114] 
Pinna, A.; Volpini, R.; Cristalli, G.; Morelli, M. New adenosine A2A receptor antagonists: Actions on Parkinson’s disease models. Eur. J. Pharmacol.,  2005, 512(2-3), 157-164.
[http://dx.doi.org/10.1016/j.ejphar.2005.01.057] [PMID: 15840400] 
[115] 
Pinna, A.; Tronci, E.; Schintu, N.; Simola, N.; Volpini, R.; Pontis, S.; Cristalli, G.; Morelli, M. A new ethyladenine antagonist of adenosine A(2A) receptors: Behavioral and biochemical characterization as an antiparkinsonian drug. Neuropharmacology,  2010, 58(3), 613-623.
[http://dx.doi.org/10.1016/j.neuropharm.2009.11.012] [PMID: 19951715] 
[116] 
Roseti, C.; Palma, E.; Martinello, K.; Fucile, S.; Morace, R.; Esposito, V.; Cantore, G.; Arcella, A.; Giangaspero, F.; Aronica, E.; Mascia, A.; Di Gennaro, G.; Quarato, P.P.; Manfredi, M.; Cristalli, G.; Lambertucci, C.; Marucci, G.; Volpini, R.; Limatola, C.; Eusebi, F. Blockage of A2A and A3 adenosine receptors decreases the desensitization of human GABA(A) receptors microtransplanted to Xenopus oocytes. Proc. Natl. Acad. Sci. USA,  2009, 106(37), 15927-15931.
[http://dx.doi.org/10.1073/pnas.0907324106] [PMID: 19721003] 
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DOI https://dx.doi.org/10.2174/0929867329666220218094501	Print ISSN 0929-8673
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Current Medicinal Chemistry

A_2A Adenosine Receptor Antagonists and their Potential in Neurological Disorders

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Current Medicinal Chemistry

A2A Adenosine Receptor Antagonists and their Potential in Neurological Disorders

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A_2A Adenosine Receptor Antagonists and their Potential in Neurological Disorders

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