Adenosine A3 receptor

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. 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.

Therapeutic implications

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

Selective Ligands

A number of selective A3 ligands are available.

Agonists/Positive Allosteric Modulators

• 2-(1-Hexynyl)-N-methyladenosine
• CF-101 (IB-MECA)/Piclidenoson
• CF-102 (2-Cl-IB-MECA)/Namodenoson
• CP-532,903
• Inosine
• LUF6000
• MRS-3558
• MRS7292
• AST-004
• CF 602

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
• ISAM-DM10

Inverse Agonists

• PSB-10

References

References

1. (February 2022). "Exploring Non-orthosteric Interactions with a Series of Potent and Selective A₃ Antagonists". ACS Medicinal Chemistry Letters.
2. Xiaowei Jin, Rebecca K. Shepherd, Brian R. Duling, and Joel Linden. [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC508491/pdf/1002849.pdf "Inosine Binds to A3 Adenosine Receptors and Stimulates Mast Cell Degranulation"]
3. 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"]
4. "Entrez Gene: ADORA3 adenosine A3 receptor".
5. (December 2006). "Docking studies of agonists and antagonists suggest an activation pathway of the A3 adenosine receptor". Journal of Molecular Graphics & Modelling.
6. (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.
7. (2005). "Development of potent and selective human A3 adenosine receptor agonists". Nucleic Acids Symposium Series.
8. (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.
9. (September 2007). "Emerging adenosine receptor agonists". Expert Opinion on Emerging Drugs.
10. (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.
11. (March 2008). "Agonist-occupied A3 adenosine receptors exist within heterogeneous complexes in membrane microdomains of individual living cells". FASEB Journal.
12. (January 2008). "Selective human adenosine A3 antagonists based on pyrido[2,1-f]purine-2,4-diones: novel features of hA3 antagonist binding". ChemMedChem.
13. (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.
14. (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.
15. (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.
16. (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.
17. (August 2008). "Synthesis and biological activities of 4-phenyl-5-pyridyl-1,3-thiazole derivatives as selective adenosine A3 antagonists". Chemical & Pharmaceutical Bulletin.
18. (December 2008). "Flexible modulation of agonist efficacy at the human A3 adenosine receptor by the imidazoquinoline allosteric enhancer LUF6000". BMC Pharmacology.
19. (January 2013). "Evaluation of SSR161421, a novel orally active adenosine A3 receptor antagonist on pharmacology models". European Journal of Pharmacology.
20. (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.