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Gene and Protein Information | ||||||
class A G protein-coupled receptor | ||||||
Species | TM | AA | Chromosomal Location | Gene Symbol | Gene Name | Reference |
Human | 7 | 412 | 22q11.23 | ADORA2A | adenosine A2a receptor | 43,72,108 |
Mouse | 7 | 410 | 10 C1 | Adora2a | adenosine A2a receptor | 85 |
Rat | 7 | 410 | 20p12 | Adora2a | adenosine A2a receptor | 22 |
Previous and Unofficial Names |
RDC8 | A2-AR | adenosine receptor A2a |
Selected 3D Structures | |||||||||||||
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Natural/Endogenous Ligands |
adenosine |
Download all structure-activity data for this target as a CSV file
Agonists | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Key to terms and symbols | View all chemical structures | Click column headers to sort | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Agonist Comments | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
The INN-assigned compound evodenoson is an agonist of the A2A receptor but affinity data is not available. Note that for tecadenoson, there is inconsistency between the two referenced articles (from the same group) as to the species origin of the ADORA2A used to generate the Ki value which is presented as identical in both articles. We have used the earlier paper as precedent, which indicates the use of the porcine receptor. |
Antagonists | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Antagonist Comments | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Some istradefylline pKi values are derived from unpublished data (Müller et al.). The human MSX-2 pKi values are derived either from experiments using recombinant receptors expressed in CHO (the higher pKi) or from native receptors in human brain tissue (the lower pKi). |
Immunopharmacology Comments |
Agonist stimulation of the A2A and A3 receptors down-regulates production of the pro-inflammatory mediators TNF-α and IL-8 in human synoviocytes [139], suggesting a role in controlling arthritic joint inflammation. Experimental evidence indicates that A2A receptor-mediated mechanisms regulate the cytokine secretion pattern of iNKT cells [100]. Arizmendi and Kulka (2018) have demonstrated that adenosine, acting via the A2A receptor, inhibits C3a-mediated activation of human mast cells through a Gαs-dependent pathway, leading the authors to conclude that this pathway may be an important regulator of mast cell activation that is a tractable target for pharmacological intervention in mast cell-mediated allergic inflammation [6]. The A2A and A2B receptors on immune cells (e.g. T cells, NK cells, dendritic cells and macrophages) mediate the immunosuppressive effects of adenosine, an action that produces a powerful tolerogenic/immunosuppressed state in the tumour microenvironment. As a result, the A2A receptor has been suggested as an immune checkpoint that produces a negative feedback loop in the tumour microenvironment, that is hypothesised to be susceptible to A2A antagonist circumvention as a novel immuno-oncology approach [76]. This could potentially repurpose A2A receptor antagonists that have failed late stage clinical trials (Phase 3) as Parkinson's disease (PD) modulators, such as istradefylline (approved in Japan, but failed to gain US FDA approval for PD), preladenant, ST-1535 and tozadenant, amongst others. A2A receptor is discussed in this immuno-oncology review [2]. The potential therapeutic combination of A2A receptor antagonists with other checkpoint inhibitors in oncology is reveiwed by Garber (2017) [46], and Table 1 therein highlights some of the A2A antagonist/checkpoint inhibitor combinations that have synergistic anti-cancer potential. Examples of A2A antagonists in early stage clinical trials in advanced malignancies: AstraZeneca's AZD4635 (compound 4g [PMID: 22220592]) in combination with anti-PD-L1 durvalumab (NCT02740985), Merck's preladenant in combination with anti-PD-L1 pembrolizumab (NCT03099161), Palobiofarma's PBF-509 ([87]) in combination with anti-PD-1 investigational mAb spartalizumab (PDR001, NCT02403193), and Corvus Pharma/Genentech's ciforadenant (CPI-444) in combination with anti-PD-L1 atezolizumab (NCT02655822). Arcus Biosciences' AB928 (structure not disclosed) is a dual A2A/2B antagonist that is in early stage immuno-oncology development [125]. AB928 activity is suggested to be peripherally restricted and is devoid of the CNS-mediated pharmacology of other adenosine receptor antagonists. |
Cell Type Associations | ||||||||
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Immuno Process Associations | ||
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Primary Transduction Mechanisms | |
Transducer | Effector/Response |
Gs family | Adenylyl cyclase stimulation |
References: 103 |
Secondary Transduction Mechanisms | |
Transducer | Effector/Response |
Gq/G11 family |
Adenylyl cyclase stimulation Phospholipase C stimulation |
Comments: A2A receptors have also been shown to couple to adenylate cyclase via Golf in the striatum [69] | |
References: 42 |
Tissue Distribution | ||||||||
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Physiological Consequences of Altering Gene Expression | ||||||||||
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Phenotypes, Alleles and Disease Models | Mouse data from MGI | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Clinically-Relevant Mutations and Pathophysiology | ||||||||||
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General Comments |
A2A antagonists can be useful as therapy for Parkinson's disease (see reviews [17,57,111]). Istradefylline (see [58] for a review) is marketed in Japan and the USA for this indication. |
1. Abo-Salem OM, Hayallah AM, Bilkei-Gorzo A, Filipek B, Zimmer A, Müller CE. (2004) Antinociceptive effects of novel A2B adenosine receptor antagonists. J Pharmacol Exp Ther, 308 (1): 358-66. [PMID:14563788]
2. Adams JL, Smothers J, Srinivasan R, Hoos A. (2015) Big opportunities for small molecules in immuno-oncology. Nat Rev Drug Discov, 14 (9): 603-22. [PMID:26228631]
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7. Baraldi PG, Tabrizi MA, Preti D, Bovero A, Romagnoli R, Fruttarolo F, Zaid NA, Moorman AR, Varani K, Gessi S et al.. (2004) Design, synthesis, and biological evaluation of new 8-heterocyclic xanthine derivatives as highly potent and selective human A2B adenosine receptor antagonists. J Med Chem, 47 (6): 1434-47. [PMID:14998332]
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