Adenosine A2A receptor

ADORA2A
A2A receptor bilayer.png
Available structures
PDBOrtholog search: PDBe RCSB
Identifiers
AliasesADORA2A, adenosine A2a receptor, A2aR, ADORA2, RDC8
External IDsOMIM: 102776 MGI: 99402 HomoloGene: 20166 GeneCards: ADORA2A
Gene location (Human)
Chromosome 22 (human)
Chr.Chromosome 22 (human)[1]
Chromosome 22 (human)
Genomic location for ADORA2A
Genomic location for ADORA2A
Band22q11.23Start24,417,879 bp[1]
End24,442,357 bp[1]
RNA expression pattern
PBB GE ADORA2A 205013 s at fs.png
More reference expression data
Orthologs
SpeciesHumanMouse
Entrez
Ensembl
UniProt
RefSeq (mRNA)

NM_000675
NM_001278497
NM_001278498
NM_001278499
NM_001278500

NM_009630
NM_001331095
NM_001331096

RefSeq (protein)

NP_000666
NP_001265426
NP_001265427
NP_001265428
NP_001265429

NP_001318024
NP_001318025
NP_033760

Location (UCSC)Chr 22: 24.42 – 24.44 MbChr 10: 75.32 – 75.33 Mb
PubMed search[3][4]
Wikidata
View/Edit HumanView/Edit Mouse

The adenosine A2A receptor, also known as ADORA2A, is an adenosine receptor, and also denotes the human gene encoding it.[5][6]

Structure[edit]

This protein is a member of the G protein-coupled receptor (GPCR) family which possess seven transmembrane alpha helices, as well as an extracellular N-terminus and an intracellular C-terminus. Furthermore, located in the intracellular side close to the membrane is a small alpha helix, often referred to as helix 8 (H8). The crystallographic structure of the adenosine A2A receptor reveals a ligand binding pocket distinct from that of other structurally determined GPCRs (i.e., the beta-2 adrenergic receptor and rhodopsin).[7] Below this primary (orthosteric) binding pocket lies a secondary (allosteric) binding pocket. The crystal-structure of A2A bound to the antagonist ZM241385 (PDB code: 4EIY) showed that a sodium-ion can be found in this location of the protein, thus giving it the name 'sodium-ion binding pocket'.[8]

Heteromers[edit]

The actions of the A2A receptor are complicated by the fact that a variety of functional heteromers composed of a mixture of A2A subunits with subunits from other unrelated G-protein coupled receptors have been found in the brain, adding a further degree of complexity to the role of adenosine in modulation of neuronal activity. Heteromers consisting of adenosine A1/A2A,[9][10] dopamine D2/A2A[11] and D3/A2A,[12] glutamate mGluR5/A2A[13] and cannabinoid CB1/A2A[14] have all been observed, as well as CB1/A2A/D2 heterotrimers,[15] and the functional significance and endogenous role of these hybrid receptors is still only starting to be unravelled.[16][17][18]

The receptor's role in immunomodulation in the context of cancer has suggested that it is an important immune checkpoint molecule.[19]

Function[edit]

The gene encodes a protein which is one of several receptor subtypes for adenosine. The activity of the encoded protein, a G protein-coupled receptor family member, is mediated by G proteins which activate adenylyl cyclase, which induce synthesis of intracellular cAMP. The A2A receptor binds with the Gs protein at the intracellular site of the receptor. The Gs protein consists of three subunits; Gsα, Gsβ and Gsγ. A crystal structure of the A2A receptor bound with the agonist NECA and a G protein-mimic has been published in 2016 (PDB code: 5g53).[20]

The encoded protein (the A2A receptor) is abundant in basal ganglia, vasculature, T lymphocytes, and platelets and it is a major target of caffeine, which is a competitive antagonist of this protein.[21]

Physiological role[edit]

A1 and A2A receptors are believed to regulate myocardial oxygen demand and to increase coronary circulation by vasodilation. In addition, A2A receptor can suppress immune cells, thereby protecting tissue from inflammation.[22]

The A2A receptor is also expressed in the brain, where it has important roles in the regulation of glutamate and dopamine release, making it a potential therapeutic target for the treatment of conditions such as insomnia, pain, depression, and Parkinson's disease.[23][24][25][26][27][28][29]

Ligands[edit]

A number of selective A2A ligands have been developed,[30][31][32][33][34][35][36][37][38][39][40][41] with several possible therapeutic applications.[42][43][44][45][46][47]

Older research on adenosine receptor function, and non-selective adenosine receptor antagonists such as aminophylline, focused mainly on the role of adenosine receptors in the heart, and led to several randomized controlled trials using these receptor antagonists to treat bradyasystolic arrest.[48][49][50][51][52][53][54]

However the development of more highly selective A2A ligands has led towards other applications, with the most significant focus of research currently being the potential therapeutic role for A2A antagonists in the treatment of Parkinson's disease.[55][56][57][58]

Agonists[edit]

Antagonists[edit]

Interactions[edit]

Adenosine A2A receptor has been shown to interact with Dopamine receptor D2.[67] As a result, Adenosine receptor A2A decreases activity in the Dopamine D2 receptors.

In cancer immunotherapy[edit]

The adenosine A2A receptor has also been shown to play a regulatory role in the adaptive immune system. In this role, A2AR functions similarly to programmed cell death-1 (PD-1) and cytotoxic t-lymphocyte associated protein-4 (CTLA-4) receptors, namely to suppress immunologic response and prevent associated tissue damage. Extracellular adenosine gathers in response to cellular stress and breakdown through interactions with hypoxia induced HIF-1α.[68] Abundant extracellular adenosine can then bind to the A2A receptor resulting in a Gs-protein coupled response, resulting in the accumulation of intracellular cAMP, which functions primarily through protein kinase A to upregulate inhibitory cytokines such as transforming growth factor-beta (TGF-β) and inhibitory receptors (i.e., PD-1).[69] Interactions with FOXP3 stimulates CD4+ T-cells into regulatory Treg cells further inhibiting immune response.[70]

Blockade of A2AR has been attempted to various ends, namely cancer immunotherapy. While several A2A receptor antagonists have progressed to clinical trials for the treatment of Parkinson's disease, A2AR blockade in the context of cancer is less characterized. Mice treated with A2AR antagonists, such as ZM241385 (listed above) or caffeine, show significantly delayed tumor growth due to T-cells resistant to inhibition.[68] This is further highlighted by A2AR knockout mice who show increased tumor rejection. Multiple checkpoint pathway inhibition has been shown to have an additive effect, as shown by an increase in response with blockade to PD-1 and CTLA-4 via monoclonal antibodies as compared to the blockade of a single pathway. Researchers believe that A2AR blockade could increase the efficacy of such treatments even further.[69] Finally, inhibition of A2AR, either through pharmacologic or genetic targeting, in chimeric antigen receptor (CAR) T-cells reveals promising results. Blockade of A2AR in this setting has shown to increase tumor clearance through CAR T-cell therapy in mice.[71] Targeting of the A2A receptor is an attractive option for the treatment of a variety of cancers, especially with the therapeutic success of the blockade of other checkpoint pathways such as PD-1 and CTLA-4.

References[edit]

  1. ^ a b c GRCh38: Ensembl release 89: ENSG00000128271 - Ensembl, May 2017
  2. ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000020178 - Ensembl, May 2017
  3. ^ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. ^ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  5. ^ Libert F, Parmentier M, Lefort A, Dinsart C, Van Sande J, Maenhaut C, et al. (May 1989). "Selective amplification and cloning of four new members of the G protein-coupled receptor family". Science. 244 (4904): 569–72. Bibcode:1989Sci...244..569L. doi:10.1126/science.2541503. PMID 2541503.
  6. ^ Libert F, Passage E, Parmentier M, Simons MJ, Vassart G, Mattei MG (September 1991). "Chromosomal mapping of A1 and A2 adenosine receptors, VIP receptor, and a new subtype of serotonin receptor". Genomics. 11 (1): 225–7. doi:10.1016/0888-7543(91)90125-X. PMID 1662665.
  7. ^ PDB: 3EML​; Jaakola VP, Griffith MT, Hanson MA, Cherezov V, Chien EY, Lane JR, et al. (November 2008). "The 2.6 angstrom crystal structure of a human A2A adenosine receptor bound to an antagonist". Science. 322 (5905): 1211–7. Bibcode:2008Sci...322.1211J. doi:10.1126/science.1164772. PMC 2586971. PMID 18832607.
  8. ^ Liu W, Chun E, Thompson AA, Chubukov P, Xu F, Katritch V, et al. (July 2012). "Structural basis for allosteric regulation of GPCRs by sodium ions". Science. 337 (6091): 232–6. Bibcode:2012Sci...337..232L. doi:10.1126/science.1219218. PMC 3399762. PMID 22798613.
  9. ^ Ciruela F, Casadó V, Rodrigues RJ, Luján R, Burgueño J, Canals M, et al. (February 2006). "Presynaptic control of striatal glutamatergic neurotransmission by adenosine A1-A2A receptor heteromers". The Journal of Neuroscience. 26 (7): 2080–7. doi:10.1523/JNEUROSCI.3574-05.2006. PMC 6674939. PMID 16481441.
  10. ^ Ferre S, Ciruela F, Borycz J, Solinas M, Quarta D, Antoniou K, et al. (January 2008). "Adenosine A1-A2A receptor heteromers: new targets for caffeine in the brain". Frontiers in Bioscience. 13 (13): 2391–9. doi:10.2741/2852. PMID 17981720.
  11. ^ Fuxe K, Ferré S, Canals M, Torvinen M, Terasmaa A, Marcellino D, et al. (2005). "Adenosine A2A and dopamine D2 heteromeric receptor complexes and their function". Journal of Molecular Neuroscience. 26 (2–3): 209–20. doi:10.1385/JMN:26:2-3:209. PMID 16012194.
  12. ^ Torvinen M, Marcellino D, Canals M, Agnati LF, Lluis C, Franco R, Fuxe K (February 2005). "Adenosine A2A receptor and dopamine D3 receptor interactions: evidence of functional A2A/D3 heteromeric complexes". Molecular Pharmacology. 67 (2): 400–7. doi:10.1124/mol.104.003376. PMID 15539641.
  13. ^ Zezula J, Freissmuth M (March 2008). "The A(2A)-adenosine receptor: a GPCR with unique features?". British Journal of Pharmacology. 153 Suppl 1 (S1): S184–90. doi:10.1038/sj.bjp.0707674. PMC 2268059. PMID 18246094.
  14. ^ Ferré S, Goldberg SR, Lluis C, Franco R (2009). "Looking for the role of cannabinoid receptor heteromers in striatal function". Neuropharmacology. 56 Suppl 1 (Suppl 1): 226–34. doi:10.1016/j.neuropharm.2008.06.076. PMC 2635338. PMID 18691604.
  15. ^ Marcellino D, Carriba P, Filip M, Borgkvist A, Frankowska M, Bellido I, et al. (April 2008). "Antagonistic cannabinoid CB1/dopamine D2 receptor interactions in striatal CB1/D2 heteromers. A combined neurochemical and behavioral analysis". Neuropharmacology. 54 (5): 815–23. doi:10.1016/j.neuropharm.2007.12.011. PMID 18262573.
  16. ^ Ferré S, Ciruela F, Quiroz C, Luján R, Popoli P, Cunha RA, et al. (November 2007). "Adenosine receptor heteromers and their integrative role in striatal function". TheScientificWorldJournal. 7: 74–85. doi:10.1100/tsw.2007.211. PMC 5901194. PMID 17982579.
  17. ^ Wardas J (May 2008). "Potential role of adenosine A2A receptors in the treatment of schizophrenia". Frontiers in Bioscience. 13 (13): 4071–96. doi:10.2741/2995. PMID 18508501.
  18. ^ Simola N, Morelli M, Pinna A (2008). "Adenosine A2A receptor antagonists and Parkinson's disease: state of the art and future directions". Current Pharmaceutical Design. 14 (15): 1475–89. doi:10.2174/138161208784480072. PMID 18537671.
  19. ^ Cekic C, Linden J (December 2014). "Adenosine A2A receptors intrinsically regulate CD8+ T cells in the tumor microenvironment". Cancer Research. 74 (24): 7239–49. doi:10.1158/0008-5472.CAN-13-3581. PMC 4459794. PMID 25341542.
  20. ^ Carpenter B, Nehmé R, Warne T, Leslie AG, Tate CG (August 2016). "Structure of the adenosine A(2A) receptor bound to an engineered G protein". Nature. 536 (7614): 104–7. Bibcode:2016Natur.536..104C. doi:10.1038/nature18966. PMC 4979997. PMID 27462812.
  21. ^ "Entrez Gene: ADORA2A adenosine A2A receptor".
  22. ^ Ohta A, Sitkovsky M (2001). "Role of G-protein-coupled adenosine receptors in downregulation of inflammation and protection from tissue damage". Nature. 414 (6866): 916–20. Bibcode:2001Natur.414..916O. doi:10.1038/414916a. PMID 11780065.
  23. ^ Hack SP, Christie MJ (2003). "Adaptations in adenosine signaling in drug dependence: therapeutic implications". Critical Reviews in Neurobiology. 15 (3–4): 235–74. doi:10.1615/CritRevNeurobiol.v15.i34.30. PMID 15248812.
  24. ^ Morelli M, Di Paolo T, Wardas J, Calon F, Xiao D, Schwarzschild MA (December 2007). "Role of adenosine A2A receptors in parkinsonian motor impairment and l-DOPA-induced motor complications". Progress in Neurobiology. 83 (5): 293–309. doi:10.1016/j.pneurobio.2007.07.001. PMID 17826884.
  25. ^ Schiffmann SN, Fisone G, Moresco R, Cunha RA, Ferré S (December 2007). "Adenosine A2A receptors and basal ganglia physiology". Progress in Neurobiology. 83 (5): 277–92. doi:10.1016/j.pneurobio.2007.05.001. PMC 2148496. PMID 17646043.
  26. ^ Ferré S, Diamond I, Goldberg SR, Yao L, Hourani SM, Huang ZL, et al. (December 2007). "Adenosine A2A receptors in ventral striatum, hypothalamus and nociceptive circuitry implications for drug addiction, sleep and pain". Progress in Neurobiology. 83 (5): 332–47. doi:10.1016/j.pneurobio.2007.04.002. PMC 2141681. PMID 17532111.
  27. ^ Brown RM, Short JL (November 2008). "Adenosine A(2A) receptors and their role in drug addiction". The Journal of Pharmacy and Pharmacology. 60 (11): 1409–30. doi:10.1211/jpp/60.11.0001. PMID 18957161.
  28. ^ Cunha RA, Ferré S, Vaugeois JM, Chen JF (2008). "Potential therapeutic interest of adenosine A2A receptors in psychiatric disorders". Current Pharmaceutical Design. 14 (15): 1512–24. doi:10.2174/138161208784480090. PMC 2423946. PMID 18537674.
  29. ^ Mingote S, Font L, Farrar AM, Vontell R, Worden LT, Stopper CM, et al. (September 2008). "Nucleus accumbens adenosine A2A receptors regulate exertion of effort by acting on the ventral striatopallidal pathway". The Journal of Neuroscience. 28 (36): 9037–46. doi:10.1523/JNEUROSCI.1525-08.2008. PMC 2806668. PMID 18768698.
  30. ^ Ongini E, Monopoli A, Cacciari B, Baraldi PG (2001). "Selective adenosine A2A receptor antagonists". Farmaco. 56 (1–2): 87–90. doi:10.1016/S0014-827X(01)01024-2. PMID 11347973.
  31. ^ Baraldi PG, Cacciari B, Romagnoli R, Spalluto G, Monopoli A, Ongini E, et al. (January 2002). "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". Journal of Medicinal Chemistry. 45 (1): 115–26. doi:10.1021/jm010924c. PMID 11754583.
  32. ^ Baraldi PG, Fruttarolo F, Tabrizi MA, Preti D, Romagnoli R, El-Kashef H, et al. (March 2003). "Design, synthesis, and biological evaluation of C9- and C2-substituted pyrazolo[4,3-e]-1,2,4-triazolo[1,5-c]pyrimidines as new A2A and A3 adenosine receptors antagonists". Journal of Medicinal Chemistry. 46 (7): 1229–41. doi:10.1021/jm021023m. PMID 12646033.
  33. ^ Weiss SM, Benwell K, Cliffe IA, Gillespie RJ, Knight AR, Lerpiniere J, et al. (December 2003). "Discovery of nonxanthine adenosine A2A receptor antagonists for the treatment of Parkinson's disease". Neurology. 61 (11 Suppl 6): S101–6. doi:10.1212/01.WNL.0000095581.20961.7D. PMID 14663021.
  34. ^ Cristalli G, Lambertucci C, Taffi S, Vittori S, Volpini R (2003). "Medicinal chemistry of adenosine A2A receptor agonists". Current Topics in Medicinal Chemistry. 3 (4): 387–401. doi:10.2174/1568026033392282. PMID 12570757. Archived from the original on 2009-05-04. Retrieved 2018-10-02.
  35. ^ Cacciari B, Pastorin G, Spalluto G (2003). "Medicinal chemistry of A2A adenosine receptor antagonists". Current Topics in Medicinal Chemistry. 3 (4): 403–11. doi:10.2174/1568026033392183. PMID 12570758. Archived from the original on 2009-05-04. Retrieved 2018-10-02.
  36. ^ Cristalli G, Cacciari B, Dal Ben D, Lambertucci C, Moro S, Spalluto G, Volpini R (March 2007). "Highlights on the development of A(2A) adenosine receptor agonists and antagonists". ChemMedChem. 2 (3): 260–81. doi:10.1002/cmdc.200600193. PMID 17177231.
  37. ^ Diniz C, Borges F, Santana L, Uriarte E, Oliveira JM, Gonçalves J, Fresco P (2008). "Ligands and therapeutic perspectives of adenosine A(2A) receptors". Current Pharmaceutical Design. 14 (17): 1698–722. doi:10.2174/138161208784746842. PMID 18673194. Archived from the original on 2009-05-04. Retrieved 2018-10-02.
  38. ^ Cristalli G, Lambertucci C, Marucci G, Volpini R, Dal Ben D (2008). "A2A adenosine receptor and its modulators: overview on a druggable GPCR and on structure-activity relationship analysis and binding requirements of agonists and antagonists". Current Pharmaceutical Design. 14 (15): 1525–52. doi:10.2174/138161208784480081. PMID 18537675.
  39. ^ Gillespie RJ, Adams DR, Bebbington D, Benwell K, Cliffe IA, Dawson CE, et al. (May 2008). "Antagonists of the human adenosine A2A receptor. Part 1: Discovery and synthesis of thieno[3,2-d]pyrimidine-4-methanone derivatives". Bioorganic & Medicinal Chemistry Letters. 18 (9): 2916–9. doi:10.1016/j.bmcl.2008.03.075. PMID 18406614.
  40. ^ Gillespie RJ, Cliffe IA, Dawson CE, Dourish CT, Gaur S, Giles PR, et al. (May 2008). "Antagonists of the human adenosine A2A receptor. Part 2: Design and synthesis of 4-arylthieno[3,2-d]pyrimidine derivatives". Bioorganic & Medicinal Chemistry Letters. 18 (9): 2920–3. doi:10.1016/j.bmcl.2008.03.076. PMID 18407496.
  41. ^ Gillespie RJ, Cliffe IA, Dawson CE, Dourish CT, Gaur S, Jordan AM, et al. (May 2008). "Antagonists of the human adenosine A2A receptor. Part 3: Design and synthesis of pyrazolo[3,4-d]pyrimidines, pyrrolo[2,3-d]pyrimidines and 6-arylpurines". Bioorganic & Medicinal Chemistry Letters. 18 (9): 2924–9. doi:10.1016/j.bmcl.2008.03.072. PMID 18411049.
  42. ^ Sullivan GW (November 2003). "Adenosine A2A receptor agonists as anti-inflammatory agents". Current Opinion in Investigational Drugs. 4 (11): 1313–9. PMID 14758770.
  43. ^ Lappas CM, Sullivan GW, Linden J (July 2005). "Adenosine A2A agonists in development for the treatment of inflammation". Expert Opinion on Investigational Drugs. 14 (7): 797–806. doi:10.1517/13543784.14.7.797. PMID 16022569.
  44. ^ El Yacoubi M, Costentin J, Vaugeois JM (December 2003). "Adenosine A2A receptors and depression". Neurology. 61 (11 Suppl 6): S82–7. doi:10.1212/01.WNL.0000095220.87550.F6. PMID 14663017.
  45. ^ Kaster MP, Rosa AO, Rosso MM, Goulart EC, Santos AR, Rodrigues AL (January 2004). "Adenosine administration produces an antidepressant-like effect in mice: evidence for the involvement of A1 and A2A receptors". Neuroscience Letters. 355 (1–2): 21–4. doi:10.1016/j.neulet.2003.10.040. PMID 14729225.
  46. ^ Takahashi RN, Pamplona FA, Prediger RD (January 2008). "Adenosine receptor antagonists for cognitive dysfunction: a review of animal studies". Frontiers in Bioscience. 13 (13): 2614–32. doi:10.2741/2870. PMID 17981738.
  47. ^ Lobato KR, Binfaré RW, Budni J, Rosa AO, Santos AR, Rodrigues AL (May 2008). "Involvement of the adenosine A1 and A2A receptors in the antidepressant-like effect of zinc in the forced swimming test". Progress in Neuro-Psychopharmacology & Biological Psychiatry. 32 (4): 994–9. doi:10.1016/j.pnpbp.2008.01.012. PMID 18289757.
  48. ^ Burton JH, Mass M, Menegazzi JJ, Yealy DM (August 1997). "Aminophylline as an adjunct to standard advanced cardiac life support in prolonged cardiac arrest". Annals of Emergency Medicine. 30 (2): 154–8. doi:10.1016/S0196-0644(97)70134-3. PMID 9250637.
  49. ^ Khoury MY, Moukarbel GV, Obeid MY, Alam SE (May 2001). "Effect of aminophylline on complete atrioventricular block with ventricular asystole following blunt chest trauma". Injury. 32 (4): 335–8. doi:10.1016/S0020-1383(00)00222-9. PMID 11325371.
  50. ^ Mader TJ, Bertolet B, Ornato JP, Gutterman JM (October 2000). "Aminophylline in the treatment of atropine-resistant bradyasystole". Resuscitation. 47 (2): 105–12. doi:10.1016/S0300-9572(00)00234-3. PMID 11008148.
  51. ^ Mader TJ, Smithline HA, Durkin L, Scriver G (March 2003). "A randomized controlled trial of intravenous aminophylline for atropine-resistant out-of-hospital asystolic cardiac arrest". Academic Emergency Medicine. 10 (3): 192–7. doi:10.1197/aemj.10.3.192. PMID 12615581.
  52. ^ Mader TJ, Gibson P (August 1997). "Adenosine receptor antagonism in refractory asystolic cardiac arrest: results of a human pilot study". Resuscitation. 35 (1): 3–7. doi:10.1016/S0300-9572(97)01097-6. PMID 9259053.
  53. ^ Perouansky M, Shamir M, Hershkowitz E, Donchin Y (July 1998). "Successful resuscitation using aminophylline in refractory cardiac arrest with asystole". Resuscitation. 38 (1): 39–41. doi:10.1016/S0300-9572(98)00079-3. PMID 9783508.
  54. ^ Viskin S, Belhassen B, Roth A, Reicher M, Averbuch M, Sheps D, et al. (February 1993). "Aminophylline for bradyasystolic cardiac arrest refractory to atropine and epinephrine". Annals of Internal Medicine. 118 (4): 279–81. doi:10.7326/0003-4819-118-4-199302150-00006. PMID 8420445.
  55. ^ Jenner P (December 2003). "A2A antagonists as novel non-dopaminergic therapy for motor dysfunction in PD". Neurology. 61 (11 Suppl 6): S32–8. doi:10.1212/01.WNL.0000095209.59347.79. PMID 14663007.
  56. ^ Mori A, Shindou T (December 2003). "Modulation of GABAergic transmission in the striatopallidal system by adenosine A2A receptors: a potential mechanism for the antiparkinsonian effects of A2A antagonists". Neurology. 61 (11 Suppl 6): S44–8. doi:10.1212/01.WNL.0000095211.71092.A0. PMID 14663009.
  57. ^ Pinna A, Wardas J, Simola N, Morelli M (November 2005). "New therapies for the treatment of Parkinson's disease: adenosine A2A receptor antagonists". Life Sciences. 77 (26): 3259–67. doi:10.1016/j.lfs.2005.04.029. PMID 15979104.
  58. ^ Kelsey JE, Langelier NA, Oriel BS, Reedy C (January 2009). "The effects of systemic, intrastriatal, and intrapallidal injections of caffeine and systemic injections of A2A and A1 antagonists on forepaw stepping in the unilateral 6-OHDA-lesioned rat". Psychopharmacology. 201 (4): 529–39. doi:10.1007/s00213-008-1319-0. PMID 18791705.
  59. ^ a b c d e f Jacobson KA, Gao ZG (March 2006). "Adenosine receptors as therapeutic targets". Nature Reviews. Drug Discovery. 5 (3): 247–64. doi:10.1038/nrd1983. PMC 3463109. PMID 16518376. table 1 lists affinities
  60. ^ Yoneyama F, Yamada H, Satoh K, Taira N (March 1992). "Vasodepressor mechanisms of 2-(1-octynyl)-adenosine (YT-146), a selective adenosine A2 receptor agonist, involve the opening of glibenclamide-sensitive K+ channels". European Journal of Pharmacology. 213 (2): 199–204. doi:10.1016/0014-2999(92)90682-T. PMID 1521559.
  61. ^ Doyle SE, Breslin FJ, Rieger JM, Beauglehole A, Lynch WJ (August 2012). "Time and sex-dependent effects of an adenosine A2A/A1 receptor antagonist on motivation to self-administer cocaine in rats". Pharmacology, Biochemistry, and Behavior. 102 (2): 257–63. doi:10.1016/j.pbb.2012.05.001. PMC 3383440. PMID 22579716.
  62. ^ Kase H, Aoyama S, Ichimura M, Ikeda K, Ishii A, Kanda T, et al. (December 2003). "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. 61 (11 Suppl 6): S97–100. doi:10.1212/01.WNL.0000095219.22086.31. PMID 14663020.
  63. ^ Mott AM, Nunes EJ, Collins LE, Port RG, Sink KS, Hockemeyer J, et al. (May 2009). "The adenosine A2A antagonist MSX-3 reverses the effects of the dopamine antagonist haloperidol on effort-related decision making in a T-maze cost/benefit procedure". Psychopharmacology. 204 (1): 103–12. doi:10.1007/s00213-008-1441-z. PMC 2875244. PMID 19132351.
  64. ^ Hodgson RA, Bertorelli R, Varty GB, Lachowicz JE, Forlani A, Fredduzzi S, et al. (July 2009). "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". The Journal of Pharmacology and Experimental Therapeutics. 330 (1): 294–303. doi:10.1124/jpet.108.149617. PMID 19332567.
  65. ^ Pinna A, Fenu S, Morelli M (March 2001). "Motor stimulant effects of the adenosine A2A receptor antagonist SCH 58261 do not develop tolerance after repeated treatments in 6-hydroxydopamine-lesioned rats". Synapse. 39 (3): 233–8. doi:10.1002/1098-2396(20010301)39:3<233::AID-SYN1004>3.0.CO;2-K. PMID 11284438.
  66. ^ Rose S, Jackson MJ, Smith LA, Stockwell K, Johnson L, Carminati P, Jenner P (September 2006). "The novel adenosine A2a receptor antagonist ST1535 potentiates the effects of a threshold dose of L-DOPA in MPTP treated common marmosets". European Journal of Pharmacology. 546 (1–3): 82–7. doi:10.1016/j.ejphar.2006.07.017. PMID 16925991.
  67. ^ Kamiya T, Saitoh O, Yoshioka K, Nakata H (June 2003). "Oligomerization of adenosine A2A and dopamine D2 receptors in living cells". Biochemical and Biophysical Research Communications. 306 (2): 544–9. doi:10.1016/S0006-291X(03)00991-4. PMID 12804599.
  68. ^ a b Sitkovsky MV, Kjaergaard J, Lukashev D, Ohta A (October 2008). "Hypoxia-adenosinergic immunosuppression: tumor protection by T regulatory cells and cancerous tissue hypoxia". Clinical Cancer Research. 14 (19): 5947–52. doi:10.1158/1078-0432.CCR-08-0229. PMID 18829471.
  69. ^ a b Leone RD, Lo YC, Powell JD (April 2015). "A2aR antagonists: Next generation checkpoint blockade for cancer immunotherapy". Computational and Structural Biotechnology Journal. 13: 265–72. doi:10.1016/j.csbj.2015.03.008. PMC 4415113. PMID 25941561.
  70. ^ Pardoll DM (March 2012). "The blockade of immune checkpoints in cancer immunotherapy". Nature Reviews. Cancer. 12 (4): 252–64. doi:10.1038/nrc3239. PMC 4856023. PMID 22437870.
  71. ^ Beavis PA, Henderson MA, Giuffrida L, Mills JK, Sek K, Cross RS, et al. (March 2017). "Targeting the adenosine 2A receptor enhances chimeric antigen receptor T cell efficacy". The Journal of Clinical Investigation. 127 (3): 929–941. doi:10.1172/JCI89455. PMC 5330718. PMID 28165340.

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