{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,10]],"date-time":"2026-04-10T16:53:33Z","timestamp":1775840013739,"version":"3.50.1"},"reference-count":104,"publisher":"MDPI AG","issue":"9","license":[{"start":{"date-parts":[[2022,4,21]],"date-time":"2022-04-21T00:00:00Z","timestamp":1650499200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"NIDDK Intramural Res. Program. University of Ferrara","award":["ZIADK031117,K.A.J.; Y1AA-3009, N.D.V."],"award-info":[{"award-number":["ZIADK031117,K.A.J.; Y1AA-3009, N.D.V."]}]},{"DOI":"10.13039\/501100007109","name":"University of Ferrara","doi-asserted-by":"publisher","award":["FIR 2017"],"award-info":[{"award-number":["FIR 2017"]}],"id":[{"id":"10.13039\/501100007109","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Molecules"],"abstract":"<jats:p>The A2A adenosine receptor is a protein belonging to a family of four GPCR adenosine receptors. It is involved in the regulation of several pathophysiological conditions in both the central nervous system and periphery. In the brain, its localization at pre- and postsynaptic level in striatum, cortex, hippocampus and its effects on glutamate release, microglia and astrocyte activation account for a crucial role in neurodegenerative diseases, including Alzheimer\u2019s disease (AD). This ailment is considered the main form of dementia and is expected to exponentially increase in coming years. The pathological tracts of AD include amyloid peptide-\u03b2 extracellular accumulation and tau hyperphosphorylation, causing neuronal cell death, cognitive deficit, and memory loss. Interestingly, in vitro and in vivo studies have demonstrated that A2A adenosine receptor antagonists may counteract each of these clinical signs, representing an important new strategy to fight a disease for which unfortunately only symptomatic drugs are available. This review offers a brief overview of the biological effects mediated by A2A adenosine receptors in AD animal and human studies and reports the state of the art of A2A adenosine receptor antagonists currently in clinical trials. As an original approach, it focuses on the crucial role of pharmacokinetics and ability to pass the blood\u2013brain barrier in the discovery of new agents for treating CNS disorders. Considering that A2A receptor antagonist istradefylline is already commercially available for Parkinson\u2019s disease treatment, if the proof of concept of these ligands in AD is confirmed and reinforced, it will be easier to offer a new hope for AD patients.<\/jats:p>","DOI":"10.3390\/molecules27092680","type":"journal-article","created":{"date-parts":[[2022,4,23]],"date-time":"2022-04-23T21:39:45Z","timestamp":1650749985000},"page":"2680","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":26,"title":["Pathophysiological Role and Medicinal Chemistry of A2A Adenosine Receptor Antagonists in Alzheimer\u2019s Disease"],"prefix":"10.3390","volume":"27","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-0839-6671","authenticated-orcid":false,"given":"Stefania","family":"Merighi","sequence":"first","affiliation":[{"name":"Department of Translational Medicine and for Romagna, University of Ferrara, 44121 Ferrara, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Pier Andrea","family":"Borea","sequence":"additional","affiliation":[{"name":"Department of Chemical, Pharmaceutical and Agricultural Sciences, University of Ferrara, 44121 Ferrara, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4562-1348","authenticated-orcid":false,"given":"Katia","family":"Varani","sequence":"additional","affiliation":[{"name":"Department of Translational Medicine and for Romagna, University of Ferrara, 44121 Ferrara, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5027-1699","authenticated-orcid":false,"given":"Fabrizio","family":"Vincenzi","sequence":"additional","affiliation":[{"name":"Department of Translational Medicine and for Romagna, University of Ferrara, 44121 Ferrara, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Alessia","family":"Travagli","sequence":"additional","affiliation":[{"name":"Department of Translational Medicine and for Romagna, University of Ferrara, 44121 Ferrara, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Manuela","family":"Nigro","sequence":"additional","affiliation":[{"name":"Department of Translational Medicine and for Romagna, University of Ferrara, 44121 Ferrara, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9442-1428","authenticated-orcid":false,"given":"Silvia","family":"Pasquini","sequence":"additional","affiliation":[{"name":"Department of Chemical, Pharmaceutical and Agricultural Sciences, University of Ferrara, 44121 Ferrara, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7693-3681","authenticated-orcid":false,"given":"R. Rama","family":"Suresh","sequence":"additional","affiliation":[{"name":"Molecular Recognition Section, Laboratory of Bioorganic Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, MD 20892, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sung Won","family":"Kim","sequence":"additional","affiliation":[{"name":"Laboratory of Neuroimaging, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD 20892, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Nora D.","family":"Volkow","sequence":"additional","affiliation":[{"name":"Laboratory of Neuroimaging, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD 20892, USA"},{"name":"National Institute on Drug Abuse, National Institutes of Health, Bethesda, MD 20892, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8104-1493","authenticated-orcid":false,"given":"Kenneth A.","family":"Jacobson","sequence":"additional","affiliation":[{"name":"Molecular Recognition Section, Laboratory of Bioorganic Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, MD 20892, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Stefania","family":"Gessi","sequence":"additional","affiliation":[{"name":"Department of Translational Medicine and for Romagna, University of Ferrara, 44121 Ferrara, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2022,4,21]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1591","DOI":"10.1152\/physrev.00049.2017","article-title":"Pharmacology of Adenosine Receptors: The State of the Art","volume":"98","author":"Borea","year":"2018","journal-title":"Physiol. Rev."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"627","DOI":"10.3389\/fphar.2018.00627","article-title":"Who Is Who in Adenosine Transport","volume":"9","year":"2018","journal-title":"Front. Pharmacol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"419","DOI":"10.1016\/j.tips.2016.02.006","article-title":"Adenosine as a Multi-Signalling Guardian Angel in Human Diseases: When, Where and How Does it Exert its Protective Effects?","volume":"37","author":"Borea","year":"2016","journal-title":"Trends Pharmacol. Sci."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"74","DOI":"10.1124\/pr.113.008540","article-title":"The A3 adenosine receptor: History and perspectives","volume":"67","author":"Borea","year":"2015","journal-title":"Pharmacol. Rev."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"771","DOI":"10.1124\/mol.58.4.771","article-title":"Adenosine A2A receptors are colocalized with and activate g(olf) in rat striatum","volume":"58","author":"Kull","year":"2000","journal-title":"Mol. Pharmacol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"29787","DOI":"10.1074\/jbc.M110.142620","article-title":"Adenosine A2A receptor signaling and golf assembly show a specific requirement for the gamma7 subtype in the striatum","volume":"285","author":"Schwindinger","year":"2010","journal-title":"J. Biol. Chem."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"813","DOI":"10.1016\/S0898-6568(03)00058-5","article-title":"Signalling from adenosine receptors to mitogen-activated protein kinases","volume":"15","author":"Schulte","year":"2003","journal-title":"Cell Signal."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"238","DOI":"10.1021\/cr0682195","article-title":"Adenosine receptor antagonists: Translating medicinal chemistry and pharmacology into clinical utility","volume":"108","author":"Baraldi","year":"2008","journal-title":"Chem. Rev."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"280","DOI":"10.1016\/j.neures.2009.08.002","article-title":"Adenosine A2a receptor induced gliosis via Akt\/NF-kappaB pathway in vitro","volume":"65","author":"Ke","year":"2009","journal-title":"Neurosci. Res."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"790","DOI":"10.1002\/med.21344","article-title":"History and perspectives of A2A adenosine receptor antagonists as potential therapeutic agents","volume":"35","author":"Preti","year":"2015","journal-title":"Med. Res. Rev."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"888","DOI":"10.3389\/fphar.2017.00888","article-title":"Inhibition of A2A Adenosine Receptor Signaling in Cancer Cells Proliferation by the Novel Antagonist TP455","volume":"8","author":"Gessi","year":"2017","journal-title":"Front. Pharmacol."},{"key":"ref_12","doi-asserted-by":"crossref","unstructured":"Jacobson, K.A., Gao, Z.G., Matricon, P., Eddy, M.T., and Carlsson, J. (2020). Adenosine A2A receptor antagonists: From caffeine to selective non-xanthines. Br. J. Pharmacol., 1\u201316.","DOI":"10.1111\/bph.15103"},{"key":"ref_13","doi-asserted-by":"crossref","unstructured":"Merighi, S., Borea, P.A., Varani, K., Vincenzi, F., Jacobson, K.A., and Gessi, S. A2A Adenosine Receptor Antagonists in Neurodegenerative Diseases. Curr. Med. Chem., 2021. in press.","DOI":"10.2174\/0929867328666211129122550"},{"key":"ref_14","unstructured":"Alzheimer\u2019s Association (2020). Alzheimer\u2019s Disease Facts and Figures. Alzheimer\u2019s & Dementia. J. Alzheimer\u2019s Assoc., 16, 391\u2013460."},{"key":"ref_15","doi-asserted-by":"crossref","unstructured":"Park, K., Kim, E., Han, H., Shim, Y., Kwon, J., Ku, B., Park, K.H., Yi, H.A., Kim, K.K., and Yang, D.W. (2017). Efficacy and Tolerability of Rivastigmine Patch Therapy in Patients with Mild-To-Moderate Alzheimer\u2019s Dementia Associated with Minimal and Moderate Ischemic white Matter Hyperintensities: A Multicenter Prospective Open-Label Clinical Trial. PLoS ONE, 12.","DOI":"10.1371\/journal.pone.0182123"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"101318","DOI":"10.1016\/j.arr.2021.101318","article-title":"Therapy for Alzheimer\u2019s disease: Missing targets and functional markers?","volume":"68","author":"Stoiljkovic","year":"2021","journal-title":"Ageing Res. Rev."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"74","DOI":"10.1016\/j.neurobiolaging.2019.10.008","article-title":"Apathy and Anxiety Are Early Markers of Alzheimer\u2019s Disease","volume":"85","author":"Johansson","year":"2020","journal-title":"Neurobiol. Aging"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"2","DOI":"10.1186\/s13024-021-00424-9","article-title":"New Approaches to Symptomatic Treatments for Alzheimer\u2019s Disease","volume":"16","author":"Cummings","year":"2021","journal-title":"Mol. Neurodegener."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"312","DOI":"10.1016\/j.cell.2019.09.001","article-title":"Alzheimer Disease: An Update on Pathobiology and Treatment Strategies","volume":"179","author":"Long","year":"2019","journal-title":"Cell"},{"key":"ref_20","first-page":"496","article-title":"FDA approval for Biogen\u2019s aducanumab sparks Alzheimer disease firestorm","volume":"20","author":"Mullard","year":"2021","journal-title":"Nat. Rev. Drug Discov."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"364","DOI":"10.1007\/s002100000313","article-title":"Structure and function of adenosine receptors and their genes","volume":"362","author":"Fredholm","year":"2000","journal-title":"Naunyn Schmiedebergs Arch. Pharmacol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"41","DOI":"10.1016\/S1877-1173(10)91002-8","article-title":"G protein-coupled receptor heteromers as new targets for drug development","volume":"91","author":"Navarro","year":"2010","journal-title":"Prog. Mol. Biol. Transl. Sci."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"1945","DOI":"10.1111\/bph.13763","article-title":"Pathological overproduction: The bad side of adenosine","volume":"174","author":"Borea","year":"2017","journal-title":"Br. J. Pharmacol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"1105","DOI":"10.3233\/JAD-201437","article-title":"Upregulation of Cortical A2A Adenosine Receptors Is Reflected in Platelets of Patients with Alzheimer\u2019s Disease","volume":"80","author":"Merighi","year":"2021","journal-title":"J. Alzheimer\u2019s Dis."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"319","DOI":"10.1016\/S0306-4522(02)00080-5","article-title":"Adenosine A2A receptor facilitation of hippocampal synaptic transmission is dependent on tonic A1 receptor inhibition","volume":"112","author":"Lopes","year":"2002","journal-title":"Neuroscience"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"104570","DOI":"10.1016\/j.nbd.2019.104570","article-title":"Synaptic and memory dysfunction in a \u03b2-amyloid model of early Alzheimer\u2019s disease depends on increased formation of ATP-derived extracellular adenosine","volume":"132","author":"Lopes","year":"2019","journal-title":"Neurobiol. Dis."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"893","DOI":"10.1016\/j.neuroscience.2005.01.014","article-title":"Different synaptic and subsynaptic localization of adenosine A2A receptors in the hippocampus and striatum of the rat","volume":"132","author":"Rebola","year":"2005","journal-title":"Neuroscience"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"121","DOI":"10.1016\/j.neuron.2007.11.023","article-title":"Adenosine A2A receptors are essential for long-term potentiation of NMDA-EPSCs at hippocampal mossy fiber synapses","volume":"57","author":"Rebola","year":"2008","journal-title":"Neuron"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"1188","DOI":"10.1111\/j.1471-4159.2005.03455.x","article-title":"Adenosine A2A receptors and metabotropic glutamate 5 receptors are co-localized and functionally interact in the hippocampus: A possible key mechanism in the modulation of N-methyl-D-aspartate effects","volume":"95","author":"Tebano","year":"2005","journal-title":"J. Neurochem."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"12","DOI":"10.1111\/j.1460-9568.2011.07719.x","article-title":"Enhanced role of adenosine A2A receptors in the modulation of LTP in the rat hippocampus upon ageing","volume":"34","author":"Costenla","year":"2011","journal-title":"Eur. J. Neurosci."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"104","DOI":"10.1089\/caff.2019.0013","article-title":"Novel Players in the Aging Synapse: Impact on Cognition","volume":"9","author":"Coelho","year":"2019","journal-title":"J. Caffeine Adenosine Res."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"572","DOI":"10.1002\/ana.410300410","article-title":"Physical basis of cognitive alterations in Alzheimer\u2019s disease: Synapse loss is the major correlate of cognitive impairment","volume":"30","author":"Terry","year":"1991","journal-title":"Ann. Neurol."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"789","DOI":"10.1126\/science.1074069","article-title":"Alzheimer\u2019s disease is a synaptic failure","volume":"298","author":"Selkoe","year":"2002","journal-title":"Science"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"1501","DOI":"10.1212\/01.wnl.0000260698.46517.8f","article-title":"Synaptic alterations in CA1 in mild Alzheimer disease and mild cognitive impairment","volume":"68","author":"Scheff","year":"2007","journal-title":"Neurology"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"1073","DOI":"10.3233\/JAD-141518","article-title":"Synaptic change in the posterior cingulate gyrus in the progression of Alzheimer\u2019s disease","volume":"43","author":"Scheff","year":"2015","journal-title":"J. Alzheimer\u2019s Dis."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"S117","DOI":"10.3233\/JAD-2010-091249","article-title":"Caffeine and coffee as therapeutics against Alzheimer\u2019s disease","volume":"20","author":"Arendash","year":"2010","journal-title":"J. Alzheimer\u2019s Dis."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"211","DOI":"10.1111\/j.1750-3639.2007.00112.x","article-title":"Up-regulation of adenosine receptors in the frontal cortex in Alzheimer\u2019s disease","volume":"18","author":"Albasanz","year":"2008","journal-title":"Brain Pathol."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"1877","DOI":"10.1016\/j.neurobiolaging.2008.01.003","article-title":"Modification upon aging of the density of presynaptic modulation systems in the hippocampus","volume":"30","author":"Canas","year":"2009","journal-title":"Neurobiol. Aging"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"509","DOI":"10.3233\/JAD-111982","article-title":"Caffeine consumption prevents memory impairment, neuronal damage, and adenosine A2A receptors upregulation in the hippocampus of a rat model of sporadic dementia","volume":"34","author":"Espinosa","year":"2013","journal-title":"J. Alzheimer\u2019s Dis."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"423","DOI":"10.1038\/nn.3930","article-title":"Astrocytic adenosine receptor A2A and Gs-coupled signaling regulate memory","volume":"18","author":"Orr","year":"2015","journal-title":"Nat. Neurosci."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"652455","DOI":"10.3389\/fphar.2021.652455","article-title":"An Open Question: Is the A2A Adenosine Receptor a Novel Target for Alzheimer\u2019s Disease Treatment?","volume":"12","author":"Merighi","year":"2021","journal-title":"Front. Pharmacol."},{"key":"ref_42","doi-asserted-by":"crossref","unstructured":"Gessi, S., Poloni, T.E., Negro, G., Varani, K., Pasquini, S., Vincenzi, F., Borea, P.A., and Merighi, S. (2021). A2A Adenosine Receptor as a Potential Biomarker and a Possible Therapeutic Target in Alzheimer\u2019s Disease. Cells, 10.","DOI":"10.3390\/cells10092344"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"1733","DOI":"10.1046\/j.1471-4159.1999.731733.x","article-title":"Increase in the number, G protein coupling, and efficiency of facilitatory adenosine A2A receptors in the limbic cortex, but not striatum, of aged rats","volume":"73","author":"Lopes","year":"1999","journal-title":"J. Neurochem."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"1295","DOI":"10.1152\/jn.00896.2002","article-title":"Enhanced adenosine A2A2A receptor facilitation of synaptic transmission in the hippocampus of aged rats","volume":"90","author":"Rebola","year":"2003","journal-title":"J. Neurophysiol."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"11915","DOI":"10.1038\/ncomms11915","article-title":"Early synaptic deficits in the APP\/PS1 mouse model of Alzheimer\u2019s disease involve neuronal adenosine A2A receptors","volume":"7","author":"Haberl","year":"2016","journal-title":"Nat. Commun."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"3831","DOI":"10.1111\/bph.13180","article-title":"Adenosine A2A receptors are necessary and sufficient to trigger memory impairment in adult mice","volume":"172","author":"Pagnussat","year":"2015","journal-title":"Br. J. Pharmacol."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"1071","DOI":"10.1016\/j.neuroscience.2008.03.038","article-title":"Caffeine prevents age-associated recognition memory decline and changes brain-derived neurotrophic factor and tirosine kinase receptor (TrkB) content in mice","volume":"153","author":"Costa","year":"2008","journal-title":"Neuroscience"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"957","DOI":"10.1016\/j.neurobiolaging.2004.08.012","article-title":"Caffeine reverses age-related deficits in olfactory discrimination and social recognition memory in rats. Involvement of adenosine A1 and A2A receptors","volume":"26","author":"Prediger","year":"2005","journal-title":"Neurobiol. Aging"},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"241","DOI":"10.1016\/j.expneurol.2006.08.008","article-title":"Caffeine and adenosine A(2a) receptor antagonists prevent beta-amyloid (25\u201335)-induced cognitive deficits in mice","volume":"203","author":"Fett","year":"2007","journal-title":"Exp. Neurol."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"2079","DOI":"10.1016\/j.neurobiolaging.2014.03.027","article-title":"Beneficial effects of caffeine in a transgenic model of Alzheimer\u2019s disease-like tau pathology","volume":"35","author":"Laurent","year":"2014","journal-title":"Neurobiol. Aging"},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"776","DOI":"10.1016\/j.expneurol.2007.11.013","article-title":"Adenosine A2A receptor blockade prevents memory dysfunction caused by beta-amyloid peptides but not by scopolamine or MK-801","volume":"210","author":"Cunha","year":"2008","journal-title":"Exp. Neurol."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"7833","DOI":"10.1073\/pnas.1423088112","article-title":"Caffeine acts through neuronal adenosine A2A receptors to prevent mood and memory dysfunction triggered by chronic stress","volume":"112","author":"Kaster","year":"2015","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"97","DOI":"10.1038\/mp.2014.151","article-title":"A2A adenosine receptor deletion is protective in a mouse model of Tauopathy","volume":"21","author":"Laurent","year":"2016","journal-title":"Mol. Psychiatry"},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"1876","DOI":"10.1038\/s41380-018-0110-9","article-title":"Age-related shift in LTD is dependent on neuronal adenosine A 2A receptors interplay with mGluR5 and NMDA receptors","volume":"25","author":"Ferreira","year":"2020","journal-title":"Mol. Psychiatry"},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"933","DOI":"10.1111\/bpa.12592","article-title":"Purine-related metabolites and their converting enzymes are altered in frontal, parietal and temporal cortex at early stages of Alzheimer\u2019s disease pathology","volume":"28","author":"Albasanz","year":"2018","journal-title":"Brain Pathol."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"149","DOI":"10.3109\/10799899209074789","article-title":"Characterization of human striatal A2-adenosine receptors using radioligand binding and photoaffinity labeling","volume":"12","author":"Ji","year":"1992","journal-title":"J. Receptor Res."},{"key":"ref_57","first-page":"882","article-title":"Adenosine A2A Receptors as Biomarkers of Brain Diseases","volume":"15","author":"Canas","year":"2021","journal-title":"Front. Neurosci."},{"key":"ref_58","doi-asserted-by":"crossref","unstructured":"Illes, P., Rubini, P., Ulrich, H., Zhao, Y., and Tang, Y. (2020). Regulation of Microglial Functions by Purinergic Mechanisms in the Healthy and Diseased CNS. Cells, 9.","DOI":"10.20944\/preprints202003.0288.v1"},{"key":"ref_59","doi-asserted-by":"crossref","unstructured":"Merighi, S., Poloni, T.E., Terrazzan, A., Moretti, E., Gessi, S., and Ferrari, D. (2021). Alzheimer and Purinergic Signaling: Just a Matter of Inflammation?. Cells, 10.","DOI":"10.3390\/cells10051267"},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"433","DOI":"10.1007\/s11302-013-9364-5","article-title":"A1R-A2AR heteromers coupled to Gs and Gi\/0 proteins modulate GABA transport into astrocytes","volume":"9","author":"Navarro","year":"2013","journal-title":"Purinergic Signal."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"555","DOI":"10.3233\/JAD-2012-120469","article-title":"Astrocytic adenosine A2A receptors control the amyloid-beta peptide-induced decrease of glutamate uptake","volume":"31","author":"Matos","year":"2012","journal-title":"J. Alzheimer\u2019s Dis."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"2329","DOI":"10.1002\/glia.23688","article-title":"A2AR-induced transcriptional deregulation in astrocytes: An in vitro study","volume":"67","author":"Paiva","year":"2019","journal-title":"Glia"},{"key":"ref_63","doi-asserted-by":"crossref","unstructured":"Franco, R., Rivas-Santisteban, R., Casanovas, M., Lillo, A., Saura, C.A., and Navarro, G. (2020). Adenosine A2A receptor antagonists affects NMDA glutamate receptor function. Potential to address neurodegeneration in Alzheimer\u2019s disease. Cells, 9.","DOI":"10.3390\/cells9051075"},{"key":"ref_64","doi-asserted-by":"crossref","unstructured":"Franco, R., Lillo, A., Rivas-Santisteban, R., Reyes-Resina, I., and Navarro, G. (2021). Microglial Adenosine Receptors: From Preconditioning to Modulating the M1\/M2 Balance in Activated Cells. Cells, 7.","DOI":"10.3390\/cells10051124"},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"919","DOI":"10.1111\/j.1471-4159.2005.03395.x","article-title":"Adenosine A2A receptor stimulation potentiates nitric oxide release by activated microglia","volume":"95","author":"Saura","year":"2005","journal-title":"J. Neurochem."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"605","DOI":"10.3389\/fneur.2018.00605","article-title":"Modulation of Microglial Activation by Adenosine A2a Receptor in Animal Models of Perinatal Brain Injury","volume":"9","author":"Colella","year":"2018","journal-title":"Front. Neurol."},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"331","DOI":"10.1002\/mdc3.12187","article-title":"Adenosine A2A Receptor Antagonists for the Treatment of Motor Symptoms in Parkinson\u2019s Disease","volume":"2","author":"Pourcher","year":"2015","journal-title":"Mov. Disord. Clin. Pract."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"12196","DOI":"10.1021\/acs.jmedchem.0c00237","article-title":"Adenosine A2A Receptor Antagonists for Cancer Immunotherapy: Miniperspective","volume":"63","author":"Yu","year":"2020","journal-title":"J. Med. Chem."},{"key":"ref_69","first-page":"113907","article-title":"Adenosine receptor antagonists: Recent advances and therapeutic perspective","volume":"68","author":"Saini","year":"2021","journal-title":"Eur. J. Med. Chem."},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"599857","DOI":"10.3389\/fphar.2020.599857","article-title":"In Vivo Positron Emission Tomography Imaging of Adenosine A2A Receptors","volume":"11","author":"Sun","year":"2020","journal-title":"Front. Pharmacol."},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"29","DOI":"10.1016\/j.nbd.2017.10.014","article-title":"Istradefylline reduces memory deficits in aging mice with amyloid pathology","volume":"110","author":"Orr","year":"2018","journal-title":"Neurobiol. Dis."},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"1821","DOI":"10.1080\/14656566.2018.1524876","article-title":"Istradefylline for the treatment of Parkinson\u2019s disease: Is it a promising strategy?","volume":"19","author":"Torti","year":"2018","journal-title":"Expert Opin. Pharmacother."},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"167","DOI":"10.1007\/s11302-020-09694-2","article-title":"The belated US FDA approval of the adenosine A2A receptor antagonist istradefylline for treatment of Parkinson\u2019s disease","volume":"16","author":"Chen","year":"2020","journal-title":"Purinergic Signal."},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"767","DOI":"10.1016\/S1474-4422(14)70148-6","article-title":"Tozadenant (SYN115) in patients with Parkinson\u2019s disease who have motor fluctuations on levodopa: A phase 2b, double-blind, randomised trial","volume":"13","author":"Hauser","year":"2014","journal-title":"Lancet"},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"55","DOI":"10.1097\/WNF.0b013e3181d137d2","article-title":"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","volume":"33","author":"Brooks","year":"2010","journal-title":"Clin. Neuropharmacol."},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"16","DOI":"10.3389\/fimmu.2021.617316","article-title":"Evaluation of Combination Strategies for the A2AR Inhibitor AZD4635 Across Tumor Microenvironment Conditions via a Systems Pharmacology Model","volume":"12","author":"Voronova","year":"2021","journal-title":"Front. Immunol."},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"530","DOI":"10.1016\/j.neo.2017.02.004","article-title":"A novel antagonist of the immune checkpoint protein adenosine A2A receptor restores tumor-infiltrating lymphocyte activity in the context of the tumor microenvironment","volume":"19","author":"Castro","year":"2017","journal-title":"Neoplasia"},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"1136","DOI":"10.1158\/2326-6066.CIR-18-0056","article-title":"A2AR antagonism with CPI-444 induces antitumor responses and augments efficacy to anti-PD-L1 and anti-CTLA-4 in preclinical models","volume":"6","author":"Willingham","year":"2018","journal-title":"Cancer Immunol. Res."},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"2562","DOI":"10.1200\/JCO.2021.39.15_suppl.2562","article-title":"Phase 1 trial of the adenosine A2A receptor antagonist inupadenant (EOS-850): Update on tolerability, and antitumor activity potentially associated with the expression of the A2A receptor within the tumor","volume":"39","author":"Buisseret","year":"2021","journal-title":"J. Clin. Oncol."},{"key":"ref_80","doi-asserted-by":"crossref","unstructured":"Franco, R., Rivas-Santisteban, R., Navarro, G., and Reyes-Resina, I. (2021). Adenosine Receptor Antagonists to Combat Cancer and to Boost Anti-Cancer Chemotherapy and Immunotherapy. Cells, 10.","DOI":"10.3390\/cells10112831"},{"key":"ref_81","unstructured":"Chen, K.X., Zhou, K., Hu, B., Xiao, M., and Chen, S. (2019). Fused Ring Derivative as A2A Receptor Inhibitor. (WO2019\/062803A1), U.S. Patent."},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"3636","DOI":"10.1093\/brain\/awz288","article-title":"Exacerbation of C1q dysregulation, synaptic loss and memory deficits in tau pathology linked to neuronal adenosine A2A receptor","volume":"142","author":"Carvalho","year":"2019","journal-title":"Brain"},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"41","DOI":"10.1097\/WNF.0000000000000073","article-title":"Japanese Istradefylline Study Group A long-term study of istradefylline safety and efficacy in patients with Parkinson disease","volume":"38","author":"Kondo","year":"2015","journal-title":"Clin. Neuropharmacol."},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"963","DOI":"10.1007\/s00210-013-0897-5","article-title":"In vitro pharmacological profile of the A2A receptor antagonist istradefylline","volume":"386","author":"Saki","year":"2013","journal-title":"Naunyn Schmiedebergs Arch. Pharmacol."},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"1138","DOI":"10.1002\/mds.25418","article-title":"Adenosine A2A receptor antagonist istradefylline reduces daily OFF time in Parkinson\u2019s disease","volume":"28","author":"Mizuno","year":"2013","journal-title":"Mov. Disord."},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"S54","DOI":"10.1016\/j.parkreldis.2020.10.027","article-title":"The challenge of developing adenosine A(2A) antagonists for Parkinson disease: Istradefylline, preladenant, and tozadenant","volume":"80","author":"LeWitt","year":"2020","journal-title":"Parkinsonism Relat. Disord."},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"399","DOI":"10.3389\/fphar.2018.00399","article-title":"The Selective Antagonism of Adenosine A2B Receptors Reduces the Synaptic Failure and Neuronal Death Induced by Oxygen and Glucose Deprivation in Rat CA1 Hippocampus In Vitro","volume":"9","author":"Fusco","year":"2018","journal-title":"Front. Pharmacol."},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"112774","DOI":"10.1016\/j.fct.2021.112774","article-title":"Pharmacokinetic, pharmacological, and genotoxic evaluation of deuterated caffeine","volume":"160","author":"Parente","year":"2022","journal-title":"Food Chem. Toxicol."},{"key":"ref_89","unstructured":"Lane, S., Green, C., Steinberg, J., Ma, L., Schmitz, J., Rathnayaka, N., Bandak, S., Ferre, S., and Moeller, F. (2012). Cardiovascular and Subjective Effects of the Novel Adenosine A(2A) Receptor Antagonist SYN115 in Cocaine Dependent Individuals. J. Addict. Res. Ther., 9."},{"key":"ref_90","doi-asserted-by":"crossref","unstructured":"Kieburtz, K., Olanow, C.W., Krishnaswami, J., Resburg, C., Kerwood, F., Glass, A., and Kenney, C. (2018). A Phase 3 Study of Tozadenant (TOZ-PD) as a Maintenance Therapy for Patients With Parkinson\u2019s Disease Experiencing Motor Fluctuations: Characterization of Study Population (P2.045). Neurology, 90.","DOI":"10.1212\/WNL.90.15_supplement.P2.045"},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"193","DOI":"10.14802\/jmd.21035","article-title":"Emerging Nondopaminergic Medications for Parkinson\u2019s Disease: Focusing on A2A Receptor Antagonists and GLP1 Receptor Agonists","volume":"14","author":"Shang","year":"2021","journal-title":"J. Mov. Disord."},{"key":"ref_92","doi-asserted-by":"crossref","first-page":"113214","DOI":"10.1016\/j.ejmech.2021.113214","article-title":"Design, synthesis and biological evaluation of Tozadenant analogues as adenosine A2A receptor ligands","volume":"214","author":"Renk","year":"2021","journal-title":"Eur. J. Med. Chem."},{"key":"ref_93","doi-asserted-by":"crossref","first-page":"33","DOI":"10.1021\/jm800961g","article-title":"Antagonists of the human A2A adenosine receptor. 4. Design, synthesis, and preclinical evaluation of 7-aryltriazolo[4,5-d]- pyrimidines","volume":"52","author":"Gillespie","year":"2009","journal-title":"J. Med. Chem."},{"key":"ref_94","doi-asserted-by":"crossref","unstructured":"Lai, T.H., Schr\u00f6der, S., Toussaint, M., Duki\u0107-Stefanovi\u0107, S., Kranz, M., Ludwig, F.A., Fischer, S., Steinbach, J., Deuther-Conrad, W., and Brust, P. (2021). Development of 18F-Labeled Radiotracers for PET Imaging of the Adenosine A2A Receptor: Synthesis, Radiolabeling and Preliminary Biological Evaluation. Int. J. Mol. Sci., 22.","DOI":"10.3390\/ijms22052285"},{"key":"ref_95","doi-asserted-by":"crossref","first-page":"294","DOI":"10.1124\/jpet.108.149617","article-title":"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-pyrazolo[4,3-e][1,2,4]- triazolo[1,5-c]pyrimidin-5-amine] in rodent models of movement disorders and depression","volume":"330","author":"Hodgson","year":"2009","journal-title":"J. Pharmacol. Exp. Ther."},{"key":"ref_96","doi-asserted-by":"crossref","first-page":"81","DOI":"10.1016\/j.cell.2020.03.003","article-title":"Impact of GPCR Structures on Drug Discovery","volume":"181","author":"Congreve","year":"2020","journal-title":"Cell"},{"key":"ref_97","doi-asserted-by":"crossref","first-page":"435","DOI":"10.1021\/cn100008c","article-title":"Moving beyond Rules: The Development of a Central Nervous System Multiparameter Optimization (CNS MPO) Approach to Enable Alignment of Druglike Properties","volume":"1","author":"Wager","year":"2010","journal-title":"ACS Chem. Neurosci."},{"key":"ref_98","doi-asserted-by":"crossref","first-page":"1292","DOI":"10.2174\/138161212799436430","article-title":"Multi-parameter optimization: Identifying high quality compounds with a balance of properties","volume":"18","author":"Segall","year":"2012","journal-title":"Curr. Pharm. Des."},{"key":"ref_99","unstructured":"(2022, February 17). Available online: https:\/\/www.optibrium.com\/downloads\/MPO_Explorer_Profile_Builder.pdf."},{"key":"ref_100","doi-asserted-by":"crossref","first-page":"680","DOI":"10.1016\/j.drudis.2014.01.005","article-title":"Finding the rules for successful drug optimisation","volume":"19","author":"Yusof","year":"2014","journal-title":"Drug Discov. Today"},{"key":"ref_101","first-page":"91","article-title":"Chapter 5. A2A adenosine receptor: Structures, modeling and medicinal chemistry","volume":"Volume 34","author":"Varani","year":"2018","journal-title":"The Adenosine Receptors, The Receptors"},{"key":"ref_102","doi-asserted-by":"crossref","first-page":"41","DOI":"10.1186\/s10194-018-0867-x","article-title":"Characterization of the trigeminovascular actions of several adenosine A2A receptor antagonists in an in vivo rat model of migraine","volume":"19","author":"Haanes","year":"2018","journal-title":"J. Headache Pain"},{"key":"ref_103","doi-asserted-by":"crossref","first-page":"2727","DOI":"10.1007\/s00259-020-05164-4","article-title":"Improved in vivo PET imaging of the adenosine A2A receptor in the brain using [18F]FLUDA, a deuterated radiotracer with high metabolic stability","volume":"48","author":"Lai","year":"2021","journal-title":"Eur. J. Nucl. Med. Mol. Imaging"},{"key":"ref_104","doi-asserted-by":"crossref","first-page":"1173","DOI":"10.3389\/fnins.2021.729153","article-title":"Effects of an Adenosine A(2A) Receptor Antagonist on Striatal Dopamine D2-Type Receptor Availability: A Randomized Control Study Using Positron Emission Tomography","volume":"15","author":"Okita","year":"2021","journal-title":"Front. Neurosci."}],"container-title":["Molecules"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1420-3049\/27\/9\/2680\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T22:58:25Z","timestamp":1760137105000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1420-3049\/27\/9\/2680"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,4,21]]},"references-count":104,"journal-issue":{"issue":"9","published-online":{"date-parts":[[2022,5]]}},"alternative-id":["molecules27092680"],"URL":"https:\/\/doi.org\/10.3390\/molecules27092680","relation":{},"ISSN":["1420-3049"],"issn-type":[{"value":"1420-3049","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,4,21]]}}}