Adenosine A3 receptor

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|date=April 2015}}.

Recent publications demonstrate that adenosine A3 receptor antagonists (SSR161421) could have therapeutic potential in bronchial asthma (17,18).

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

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.

A number of selective A₃ ligands are available.{{cite journal | vauthors = Miranda-Pastoriza D, Bernárdez R, Azuaje J, Prieto-Díaz R, Majellaro M, Tamhankar AV, Koenekoop L, González A, Gioé-Gallo C, Mallo-Abreu A, Brea J, Loza MI, García-Rey A, García-Mera X, Gutiérrez-de-Terán H, Sotelo E | display-authors = 6 | title = Exploring Non-orthosteric Interactions with a Series of Potent and Selective A₃ Antagonists | journal = ACS Medicinal Chemistry Letters | volume = 13 | issue = 2 | pages = 243–249 | date = February 2022 | pmid = 35178181 | doi = 10.1021/acsmedchemlett.1c00598 | pmc = 8842279 }}

• 2-(1-Hexynyl)-N-methyladenosine
• CF-101 (IB-MECA)/Piclidenoson
• CF-102 (2-Cl-IB-MECA)/Namodenoson
• CP-532,903
• InosineXiaowei 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"]
• LUF6000Courtney 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. [ "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"]
• MRS-3558
• MRS7292
• AST-004
• CF 602

• 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

• PSB-10

{{reflist|colwidth=35em|refs=

{{cite web | title = Entrez Gene: ADORA3 adenosine A3 receptor| url = https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=140}}

{{cite journal | vauthors = Kim SK, Gao ZG, Jeong LS, Jacobson KA | title = Docking studies of agonists and antagonists suggest an activation pathway of the A3 adenosine receptor | journal = Journal of Molecular Graphics & Modelling | volume = 25 | issue = 4 | pages = 562–577 | date = December 2006 | pmid = 16793299 | pmc = 6262875 | doi = 10.1016/j.jmgm.2006.05.004 }}

{{cite journal | vauthors = Ge ZD, Peart JN, Kreckler LM, Wan TC, Jacobson MA, Gross GJ, Auchampach JA | title = Cl-IB-MECA [2-chloro-N6-(3-iodobenzyl)adenosine-5'-N-methylcarboxamide] reduces ischemia/reperfusion injury in mice by activating the A3 adenosine receptor | journal = The Journal of Pharmacology and Experimental Therapeutics | volume = 319 | issue = 3 | pages = 1200–1210 | date = December 2006 | pmid = 16985166 | pmc = 2430759 | doi = 10.1124/jpet.106.111351 }}

{{cite journal | vauthors = Jeong LS, Lee HW, Jacobson KA, Lee SK, Chun MW | title = Development of potent and selective human A3 adenosine receptor agonists | journal = Nucleic Acids Symposium Series | volume = 49 | issue = 49 | pages = 31–32 | year = 2005 | pmid = 17150618 | doi = 10.1093/nass/49.1.31 | doi-access = free }}

{{cite journal | vauthors = Bevan N, Butchers PR, Cousins R, Coates J, Edgar EV, Morrison V, Sheehan MJ, Reeves J, Wilson DJ | display-authors = 6 | title = 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 | journal = European Journal of Pharmacology | volume = 564 | issue = 1–3 | pages = 219–225 | date = June 2007 | pmid = 17382926 | doi = 10.1016/j.ejphar.2007.01.094 }}

{{cite journal | vauthors = Gao ZG, Jacobson KA | title = Emerging adenosine receptor agonists | journal = Expert Opinion on Emerging Drugs | volume = 12 | issue = 3 | pages = 479–492 | date = September 2007 | pmid = 17874974 | doi = 10.1517/14728214.12.3.479 | s2cid = 13777846 | url = https://zenodo.org/record/1236313 | pmc = 11790296 }}

{{cite journal | vauthors = Wan TC, Ge ZD, Tampo A, Mio Y, Bienengraeber MW, Tracey WR, Gross GJ, Kwok WM, Auchampach JA | display-authors = 6 | title = 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 | journal = The Journal of Pharmacology and Experimental Therapeutics | volume = 324 | issue = 1 | pages = 234–243 | date = January 2008 | pmid = 17906066 | pmc = 2435594 | doi = 10.1124/jpet.107.127480 }}

{{cite journal | vauthors = Cordeaux Y, Briddon SJ, Alexander SP, Kellam B, Hill SJ | title = Agonist-occupied A3 adenosine receptors exist within heterogeneous complexes in membrane microdomains of individual living cells | journal = FASEB Journal | volume = 22 | issue = 3 | pages = 850–860 | date = March 2008 | pmid = 17959910 | doi = 10.1096/fj.07-8180com | doi-access = free | s2cid = 10705640 }}

{{cite journal | vauthors = Priego EM, Pérez-Pérez MJ, von Frijtag Drabbe Kuenzel JK, de Vries H, Ijzerman AP, Camarasa MJ, Martín-Santamaría S | title = Selective human adenosine A3 antagonists based on pyrido[2,1-f]purine-2,4-diones: novel features of hA3 antagonist binding | journal = ChemMedChem | volume = 3 | issue = 1 | pages = 111–119 | date = January 2008 | pmid = 18000937 | doi = 10.1002/cmdc.200700173 | s2cid = 7128294 | hdl = 10261/82277 }}

{{cite journal | vauthors = Silverman MH, Strand V, Markovits D, Nahir M, Reitblat T, Molad Y, Rosner I, Rozenbaum M, Mader R, Adawi M, Caspi D, Tishler M, Langevitz P, Rubinow A, Friedman J, Green L, Tanay A, Ochaion A, Cohen S, Kerns WD, Cohn I, Fishman-Furman S, Farbstein M, Yehuda SB, Fishman P | display-authors = 6 | title = Clinical evidence for utilization of the A3 adenosine receptor as a target to treat rheumatoid arthritis: data from a phase II clinical trial | journal = The Journal of Rheumatology | volume = 35 | issue = 1 | pages = 41–48 | date = January 2008 | pmid = 18050382 | url = http://www.jrheum.org/content/35/1/41.abstract }}

{{cite journal | vauthors = Jeong LS, Lee HW, Kim HO, Tosh DK, Pal S, Choi WJ, Gao ZG, Patel AR, Williams W, Jacobson KA, Kim HD | display-authors = 6 | title = Structure-activity relationships of 2-chloro-N6-substituted-4'-thioadenosine-5'-N,N-dialkyluronamides as human A3 adenosine receptor antagonists | journal = Bioorganic & Medicinal Chemistry Letters | volume = 18 | issue = 5 | pages = 1612–1616 | date = March 2008 | pmid = 18255292 | pmc = 8611656 | doi = 10.1016/j.bmcl.2008.01.070 }}

{{cite journal | vauthors = Gao ZG, Jacobson KA | title = Translocation of arrestin induced by human A(3) adenosine receptor ligands in an engineered cell line: comparison with G protein-dependent pathways | journal = Pharmacological Research | volume = 57 | issue = 4 | pages = 303–311 | date = April 2008 | pmid = 18424164 | pmc = 2409065 | doi = 10.1016/j.phrs.2008.02.008 }}

{{cite journal | vauthors = Bar-Yehuda S, Stemmer SM, Madi L, Castel D, Ochaion A, Cohen S, Barer F, Zabutti A, Perez-Liz G, Del Valle L, Fishman P | display-authors = 6 | title = The A3 adenosine receptor agonist CF102 induces apoptosis of hepatocellular carcinoma via de-regulation of the Wnt and NF-kappaB signal transduction pathways | journal = International Journal of Oncology | volume = 33 | issue = 2 | pages = 287–295 | date = August 2008 | pmid = 18636149 | doi = 10.3892/ijo_00000008 | doi-access = free }}

{{cite journal | vauthors = Miwatashi S, Arikawa Y, Matsumoto T, Uga K, Kanzaki N, Imai YN, Ohkawa S | title = Synthesis and biological activities of 4-phenyl-5-pyridyl-1,3-thiazole derivatives as selective adenosine A3 antagonists | journal = Chemical & Pharmaceutical Bulletin | volume = 56 | issue = 8 | pages = 1126–1137 | date = August 2008 | pmid = 18670113 | doi = 10.1248/cpb.56.1126 | doi-access = free }}

{{cite journal | vauthors = Gao ZG, Ye K, Göblyös A, Ijzerman AP, Jacobson KA | title = Flexible modulation of agonist efficacy at the human A3 adenosine receptor by the imidazoquinoline allosteric enhancer LUF6000 | journal = BMC Pharmacology | volume = 8 | pages = 20 | date = December 2008 | pmid = 19077268 | pmc = 2625337 | doi = 10.1186/1471-2210-8-20 | doi-access = free }}

{{cite journal | vauthors = Mikus EG, Szeredi J, Boer K, Tímári G, Finet M, Aranyi P, Galzin AM | title = Evaluation of SSR161421, a novel orally active adenosine A3 receptor antagonist on pharmacology models | journal = European Journal of Pharmacology | volume = 699 | issue = 1–3 | pages = 172–179 | date = January 2013 | pmid = 23219796 | doi = 10.1016/j.ejphar.2012.11.049 }}

{{cite journal | vauthors = Mikus EG, Boér K, Timári G, Urbán-Szabó K, Kapui Z, Szeredi J, Gerber K, Szabó T, Bátori S, Finet M, Arányi P, Galzin AM | display-authors = 6 | title = Interaction of SSR161421, a novel specific adenosine A(3) receptor antagonist with adenosine A(3) receptor agonists both in vitro and in vivo | journal = European Journal of Pharmacology | volume = 699 | issue = 1–3 | pages = 62–66 | date = January 2013 | pmid = 23219789 | doi = 10.1016/j.ejphar.2012.11.046 }}

}}

{{refbegin |colwidth=35em}}

• {{cite journal | vauthors = Klotz KN | title = Adenosine receptors and their ligands | journal = Naunyn-Schmiedeberg's Archives of Pharmacology | volume = 362 | issue = 4–5 | pages = 382–391 | date = November 2000 | pmid = 11111832 | doi = 10.1007/s002100000315 | s2cid = 12938732 }}
• {{cite journal | vauthors = Monitto CL, Levitt RC, DiSilvestre D, Holroyd KJ | title = Localization of the A3 adenosine receptor gene (ADORA3) to human chromosome 1p | journal = Genomics | volume = 26 | issue = 3 | pages = 637–638 | date = April 1995 | pmid = 7607699 | doi = 10.1016/0888-7543(95)80194-Q | doi-access = free }}
• {{cite journal | vauthors = Salvatore CA, Jacobson MA, Taylor HE, Linden J, Johnson RG | title = Molecular cloning and characterization of the human A3 adenosine receptor | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 90 | issue = 21 | pages = 10365–10369 | date = November 1993 | pmid = 8234299 | pmc = 47775 | doi = 10.1073/pnas.90.21.10365 | doi-access = free | bibcode = 1993PNAS...9010365S }}
• {{cite journal | vauthors = Sajjadi FG, Firestein GS | title = cDNA cloning and sequence analysis of the human A3 adenosine receptor | journal = Biochimica et Biophysica Acta (BBA) - Molecular Cell Research | volume = 1179 | issue = 1 | pages = 105–107 | date = October 1993 | pmid = 8399349 | doi = 10.1016/0167-4889(93)90077-3 }}
• {{cite journal | vauthors = Murrison EM, Goodson SJ, Edbrooke MR, Harris CA | title = Cloning and characterisation of the human adenosine A3 receptor gene | journal = FEBS Letters | volume = 384 | issue = 3 | pages = 243–246 | date = April 1996 | pmid = 8617363 | doi = 10.1016/0014-5793(96)00324-9 | s2cid = 3170758 | doi-access = free }}
• {{cite journal | vauthors = Bonaldo MF, Lennon G, Soares MB | title = Normalization and subtraction: two approaches to facilitate gene discovery | journal = Genome Research | volume = 6 | issue = 9 | pages = 791–806 | date = September 1996 | pmid = 8889548 | doi = 10.1101/gr.6.9.791 | doi-access = free }}
• {{cite journal | vauthors = Bouma MG, Jeunhomme TM, Boyle DL, Dentener MA, Voitenok NN, van den Wildenberg FA, Buurman WA | title = Adenosine inhibits neutrophil degranulation in activated human whole blood: involvement of adenosine A2 and A3 receptors | journal = Journal of Immunology | volume = 158 | issue = 11 | pages = 5400–5408 | date = June 1997 | doi = 10.4049/jimmunol.158.11.5400 | pmid = 9164961 | s2cid = 9984303 | doi-access = free }}
• {{cite journal | vauthors = Atkinson MR, Townsend-Nicholson A, Nicholl JK, Sutherland GR, Schofield PR | title = Cloning, characterisation and chromosomal assignment of the human adenosine A3 receptor (ADORA3) gene | journal = Neuroscience Research | volume = 29 | issue = 1 | pages = 73–79 | date = September 1997 | pmid = 9293494 | doi = 10.1016/S0168-0102(97)00073-4 | s2cid = 36060683 }}
• {{cite journal | vauthors = Palmer TM, Harris CA, Coote J, Stiles GL | title = Induction of multiple effects on adenylyl cyclase regulation by chronic activation of the human A3 adenosine receptor | journal = Molecular Pharmacology | volume = 52 | issue = 4 | pages = 632–640 | date = October 1997 | pmid = 9380026 | doi = 10.1124/mol.52.4.632 | s2cid = 2170191 }}
• {{cite journal | vauthors = Liang BT, Jacobson KA | title = A physiological role of the adenosine A3 receptor: sustained cardioprotection | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 95 | issue = 12 | pages = 6995–6999 | date = June 1998 | pmid = 9618527 | pmc = 22715 | doi = 10.1073/pnas.95.12.6995 | doi-access = free | bibcode = 1998PNAS...95.6995L }}
• {{cite journal | vauthors = Dougherty C, Barucha J, Schofield PR, Jacobson KA, Liang BT | title = Cardiac myocytes rendered ischemia resistant by expressing the human adenosine A1 or A3 receptor | journal = FASEB Journal | volume = 12 | issue = 15 | pages = 1785–1792 | date = December 1998 | pmid = 9837869 | pmc = 5550893 | doi = 10.1096/fasebj.12.15.1785 | doi-access = free }}
• {{cite journal | vauthors = Murphy WJ, Eizirik E, Johnson WE, Zhang YP, Ryder OA, O'Brien SJ | title = Molecular phylogenetics and the origins of placental mammals | journal = Nature | volume = 409 | issue = 6820 | pages = 614–618 | date = February 2001 | pmid = 11214319 | doi = 10.1038/35054550 | s2cid = 4373847 | bibcode = 2001Natur.409..614M }}
• {{cite journal | vauthors = Gao ZG, Chen A, Barak D, Kim SK, Müller CE, Jacobson KA | title = Identification by site-directed mutagenesis of residues involved in ligand recognition and activation of the human A3 adenosine receptor | journal = The Journal of Biological Chemistry | volume = 277 | issue = 21 | pages = 19056–19063 | date = May 2002 | pmid = 11891221 | pmc = 5602557 | doi = 10.1074/jbc.M110960200 | doi-access = free }}
• {{cite journal | vauthors = Broussas M, Cornillet-Lefèbvre P, Potron G, Nguyên P | title = Adenosine inhibits tissue factor expression by LPS-stimulated human monocytes: involvement of the A3 adenosine receptor | journal = Thrombosis and Haemostasis | volume = 88 | issue = 1 | pages = 123–130 | date = July 2002 | pmid = 12152652 | doi = 10.1055/s-0037-1613164 | s2cid = 3118696 }}
• {{cite journal | vauthors = Merighi S, Mirandola P, Milani D, Varani K, Gessi S, Klotz KN, Leung E, Baraldi PG, Borea PA | display-authors = 6 | title = Adenosine receptors as mediators of both cell proliferation and cell death of cultured human melanoma cells | journal = The Journal of Investigative Dermatology | volume = 119 | issue = 4 | pages = 923–933 | date = October 2002 | pmid = 12406340 | doi = 10.1046/j.1523-1747.2002.00111.x | doi-access = free }}
• {{cite journal | vauthors = Trincavelli ML, Tuscano D, Marroni M, Falleni A, Gremigni V, Ceruti S, Abbracchio MP, Jacobson KA, Cattabeni F, Martini C | display-authors = 6 | title = A3 adenosine receptors in human astrocytoma cells: agonist-mediated desensitization, internalization, and down-regulation | journal = Molecular Pharmacology | volume = 62 | issue = 6 | pages = 1373–1384 | date = December 2002 | pmid = 12435805 | pmc = 4806643 | doi = 10.1124/mol.62.6.1373 }}
• {{cite journal | vauthors = Strausberg RL, Feingold EA, Grouse LH, Derge JG, Klausner RD, Collins FS, Wagner L, Shenmen CM, Schuler GD, Altschul SF, Zeeberg B, Buetow KH, Schaefer CF, Bhat NK, Hopkins RF, Jordan H, Moore T, Max SI, Wang J, Hsieh F, Diatchenko L, Marusina K, Farmer AA, Rubin GM, Hong L, Stapleton M, Soares MB, Bonaldo MF, Casavant TL, Scheetz TE, Brownstein MJ, Usdin TB, Toshiyuki S, Carninci P, Prange C, Raha SS, Loquellano NA, Peters GJ, Abramson RD, Mullahy SJ, Bosak SA, McEwan PJ, McKernan KJ, Malek JA, Gunaratne PH, Richards S, Worley KC, Hale S, Garcia AM, Gay LJ, Hulyk SW, Villalon DK, Muzny DM, Sodergren EJ, Lu X, Gibbs RA, Fahey J, Helton E, Ketteman M, Madan A, Rodrigues S, Sanchez A, Whiting M, Madan A, Young AC, Shevchenko Y, Bouffard GG, Blakesley RW, Touchman JW, Green ED, Dickson MC, Rodriguez AC, Grimwood J, Schmutz J, Myers RM, Butterfield YS, Krzywinski MI, Skalska U, Smailus DE, Schnerch A, Schein JE, Jones SJ, Marra MA | display-authors = 6 | title = Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 99 | issue = 26 | pages = 16899–16903 | date = December 2002 | pmid = 12477932 | pmc = 139241 | doi = 10.1073/pnas.242603899 | doi-access = free | bibcode = 2002PNAS...9916899M }}
• {{cite journal | vauthors = Feoktistov I, Ryzhov S, Goldstein AE, Biaggioni I | title = Mast cell-mediated stimulation of angiogenesis: cooperative interaction between A2B and A3 adenosine receptors | journal = Circulation Research | volume = 92 | issue = 5 | pages = 485–492 | date = March 2003 | pmid = 12600879 | doi = 10.1161/01.RES.0000061572.10929.2D | doi-access = free }}
• {{cite journal | vauthors = Gao ZG, Kim SK, Gross AS, Chen A, Blaustein JB, Jacobson KA | title = Identification of essential residues involved in the allosteric modulation of the human A(3) adenosine receptor | journal = Molecular Pharmacology | volume = 63 | issue = 5 | pages = 1021–1031 | date = May 2003 | pmid = 12695530 | pmc = 4367541 | doi = 10.1124/mol.63.5.1021 }}

{{refend}}

• {{cite web | url = http://www.iuphar-db.org/GPCR/ReceptorDisplayForward?receptorID=2172 | title = Adenosine Receptors: A₃ | work = IUPHAR Database of Receptors and Ion Channels | publisher = International Union of Basic and Clinical Pharmacology | access-date = 2008-11-25 | archive-date = 2020-11-30 | archive-url = https://web.archive.org/web/20201130073403/https://www.iuphar-db.org/GPCR/ReceptorDisplayForward?receptorID=2172 | url-status = dead }}
• {{UCSC gene info|ADORA3}}

{{G protein-coupled receptors}}

{{Adenosinergics}}

Category:Adenosine receptors