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Adenosine A3 receptor

ADORA3
Available structures
PDBOrtholog search: PDBe RCSB
Identifiers
AliasesADORA3, A3AR, AD026, bA552M11.5, adenosine A3 receptor
External IDsOMIM: 600445; MGI: 104847; HomoloGene: 550; GeneCards: ADORA3; OMA:ADORA3 - orthologs
Orthologs
SpeciesHumanMouse
Entrez

140

11542

Ensembl

ENSG00000282608

ENSMUSG00000000562

UniProt

P0DMS8

Q61618
Q3U4C5

RefSeq (mRNA)

NM_001302679
NM_000677
NM_001302678

NM_009631

RefSeq (protein)

NP_000668
NP_001289607
NP_001289608

NP_033761

Location (UCSC)Chr 1: 111.5 – 111.5 MbChr 3: 105.78 – 105.82 Mb
PubMed search[3][4]
Wikidata
View/Edit HumanView/Edit Mouse

The adenosine A3 receptor, also known as ADORA3, is an adenosine receptor, but also denotes the human gene encoding it.

Function

Adenosine A3 receptors are G protein-coupled receptors that couple to Gi/Gq and are involved in a variety of intracellular signaling pathways and physiological functions. It mediates a sustained cardioprotective function during cardiac ischemia, it is involved in the inhibition of neutrophil degranulation in neutrophil-mediated tissue injury, it has been implicated in both neuroprotective and neurodegenerative effects, and it may also mediate both cell proliferation and cell death[citation needed]. Recent publications demonstrate that adenosine A3 receptor antagonists (SSR161421) could have therapeutic potential in bronchial asthma (17,18).

Gene

Multiple transcript variants encoding different isoforms have been found for this gene.[5]

Therapeutic implications

An adenosine A3 receptor agonist (CF-101) is in clinical trials for the treatment of rheumatoid arthritis.[6] In a mouse model of infarction the A3 selective agonist CP-532,903 protected against myocardial ischemia and reperfusion injury.[7]

Selective Ligands

A number of selective A3 ligands are available.[8][9][10][11][12][13][14][15][16][17][18][19][20]

Agonists/Positive Allosteric Modulators

Antagonists/Negative Allosteric Modulators

  • KF-26777
  • MRS-545
  • MRS-1191
  • MRS-1220
  • MRS-1334
  • MRS-1523
  • MRS-3777
  • MRE-3005-F20
  • MRE-3008-F20
  • PSB-11
  • OT-7999
  • VUF-5574
  • SSR161421[23][24]
  • ISAM-DM10

Inverse Agonists

References

  1. ^ a b c GRCh38: Ensembl release 89: ENSG00000282608 – Ensembl, May 2017
  2. ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000000562 – 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. ^ "Entrez Gene: ADORA3 adenosine A3 receptor".
  6. ^ Silverman MH, Strand V, Markovits D, Nahir M, Reitblat T, Molad Y, et al. (January 2008). "Clinical evidence for utilization of the A3 adenosine receptor as a target to treat rheumatoid arthritis: data from a phase II clinical trial". The Journal of Rheumatology. 35 (1): 41–48. PMID 18050382.
  7. ^ Wan TC, Ge ZD, Tampo A, Mio Y, Bienengraeber MW, Tracey WR, et al. (January 2008). "The A3 adenosine receptor agonist CP-532,903 [N6-(2,5-dichlorobenzyl)-3'-aminoadenosine-5'-N-methylcarboxamide] protects against myocardial ischemia/reperfusion injury via the sarcolemmal ATP-sensitive potassium channel". The Journal of Pharmacology and Experimental Therapeutics. 324 (1): 234–243. doi:10.1124/jpet.107.127480. PMC 2435594. PMID 17906066.
  8. ^ Jeong LS, Lee HW, Jacobson KA, Lee SK, Chun MW (2005). "Development of potent and selective human A3 adenosine receptor agonists". Nucleic Acids Symposium Series. 49 (49): 31–32. doi:10.1093/nass/49.1.31. PMID 17150618.
  9. ^ Gao ZG, Jacobson KA (September 2007). "Emerging adenosine receptor agonists". Expert Opinion on Emerging Drugs. 12 (3): 479–492. doi:10.1517/14728214.12.3.479. PMID 17874974. S2CID 13777846.
  10. ^ Kim SK, Gao ZG, Jeong LS, Jacobson KA (December 2006). "Docking studies of agonists and antagonists suggest an activation pathway of the A3 adenosine receptor". Journal of Molecular Graphics & Modelling. 25 (4): 562–577. doi:10.1016/j.jmgm.2006.05.004. PMC 6262875. PMID 16793299.
  11. ^ Ge ZD, Peart JN, Kreckler LM, Wan TC, Jacobson MA, Gross GJ, Auchampach JA (December 2006). "Cl-IB-MECA [2-chloro-N6-(3-iodobenzyl)adenosine-5'-N-methylcarboxamide] reduces ischemia/reperfusion injury in mice by activating the A3 adenosine receptor". The Journal of Pharmacology and Experimental Therapeutics. 319 (3): 1200–1210. doi:10.1124/jpet.106.111351. PMC 2430759. PMID 16985166.
  12. ^ Bevan N, Butchers PR, Cousins R, Coates J, Edgar EV, Morrison V, et al. (June 2007). "Pharmacological characterisation and inhibitory effects of (2R,3R,4S,5R)-2-(6-amino-2-{[(1S)-2-hydroxy-1-(phenylmethyl)ethyl]amino}-9H-purin-9-yl)-5-(2-ethyl-2H-tetrazol-5-yl)tetrahydro-3,4-furandiol, a novel ligand that demonstrates both adenosine A(2A) receptor agonist and adenosine A(3) receptor antagonist activity". European Journal of Pharmacology. 564 (1–3): 219–225. doi:10.1016/j.ejphar.2007.01.094. PMID 17382926.
  13. ^ Priego EM, Pérez-Pérez MJ, von Frijtag Drabbe Kuenzel JK, de Vries H, Ijzerman AP, Camarasa MJ, Martín-Santamaría S (January 2008). "Selective human adenosine A3 antagonists based on pyrido[2,1-f]purine-2,4-diones: novel features of hA3 antagonist binding". ChemMedChem. 3 (1): 111–119. doi:10.1002/cmdc.200700173. hdl:10261/82277. PMID 18000937. S2CID 7128294.
  14. ^ Jeong LS, Lee HW, Kim HO, Tosh DK, Pal S, Choi WJ, et al. (March 2008). "Structure-activity relationships of 2-chloro-N6-substituted-4'-thioadenosine-5'-N,N-dialkyluronamides as human A3 adenosine receptor antagonists". Bioorganic & Medicinal Chemistry Letters. 18 (5): 1612–1616. doi:10.1016/j.bmcl.2008.01.070. PMC 8611656. PMID 18255292.
  15. ^ Cordeaux Y, Briddon SJ, Alexander SP, Kellam B, Hill SJ (March 2008). "Agonist-occupied A3 adenosine receptors exist within heterogeneous complexes in membrane microdomains of individual living cells". FASEB Journal. 22 (3): 850–860. doi:10.1096/fj.07-8180com. PMID 17959910. S2CID 10705640.
  16. ^ Gao ZG, Jacobson KA (April 2008). "Translocation of arrestin induced by human A(3) adenosine receptor ligands in an engineered cell line: comparison with G protein-dependent pathways". Pharmacological Research. 57 (4): 303–311. doi:10.1016/j.phrs.2008.02.008. PMC 2409065. PMID 18424164.
  17. ^ Miwatashi S, Arikawa Y, Matsumoto T, Uga K, Kanzaki N, Imai YN, Ohkawa S (August 2008). "Synthesis and biological activities of 4-phenyl-5-pyridyl-1,3-thiazole derivatives as selective adenosine A3 antagonists". Chemical & Pharmaceutical Bulletin. 56 (8): 1126–1137. doi:10.1248/cpb.56.1126. PMID 18670113.
  18. ^ Gao ZG, Ye K, Göblyös A, Ijzerman AP, Jacobson KA (December 2008). "Flexible modulation of agonist efficacy at the human A3 adenosine receptor by the imidazoquinoline allosteric enhancer LUF6000". BMC Pharmacology. 8: 20. doi:10.1186/1471-2210-8-20. PMC 2625337. PMID 19077268.
  19. ^ Bar-Yehuda S, Stemmer SM, Madi L, Castel D, Ochaion A, Cohen S, et al. (August 2008). "The A3 adenosine receptor agonist CF102 induces apoptosis of hepatocellular carcinoma via de-regulation of the Wnt and NF-kappaB signal transduction pathways". International Journal of Oncology. 33 (2): 287–295. doi:10.3892/ijo_00000008. PMID 18636149.
  20. ^ Miranda-Pastoriza D, Bernárdez R, Azuaje J, Prieto-Díaz R, Majellaro M, Tamhankar AV, et al. (February 2022). "Exploring Non-orthosteric Interactions with a Series of Potent and Selective A3 Antagonists". ACS Medicinal Chemistry Letters. 13 (2): 243–249. doi:10.1021/acsmedchemlett.1c00598. PMC 8842279. PMID 35178181.
  21. ^ Xiaowei Jin, Rebecca K. Shepherd, Brian R. Duling, and Joel Linden. "Inosine Binds to A3 Adenosine Receptors and Stimulates Mast Cell Degranulation"
  22. ^ Courtney L. Fisher, Matteo Pavan, Veronica Salmaso, Robert F. Keyes, Tina C. Wan, Balaram Pradhan, Zhan-Guo Gao, Brian C. Smith, Kenneth A. Jacobson and John A. Auchampach. [<https://doi.org/10.1124/molpharm.123.000784> "Extrahelical binding site for a 1H-imidazo[4,5-c]quinolin-4-amine A3 adenosine receptor positive allosteric modulator on helix 8 and distal portions of transmembrane domains 1 and 7"]
  23. ^ Mikus EG, Szeredi J, Boer K, Tímári G, Finet M, Aranyi P, Galzin AM (January 2013). "Evaluation of SSR161421, a novel orally active adenosine A3 receptor antagonist on pharmacology models". European Journal of Pharmacology. 699 (1–3): 172–179. doi:10.1016/j.ejphar.2012.11.049. PMID 23219796.
  24. ^ Mikus EG, Boér K, Timári G, Urbán-Szabó K, Kapui Z, Szeredi J, et al. (January 2013). "Interaction of SSR161421, a novel specific adenosine A(3) receptor antagonist with adenosine A(3) receptor agonists both in vitro and in vivo". European Journal of Pharmacology. 699 (1–3): 62–66. doi:10.1016/j.ejphar.2012.11.046. PMID 23219789.

Further reading
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