Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

Adenosine receptors as therapeutic targets

Nature Reviews Drug Discovery volume 5, pages 247–264 (2006)Cite this article

Key Points

  • Modulation of adenosine receptors (ARs) using selective agonists and antagonists is a promising therapeutic strategy for the treatment of diseases and disorders of the cardiovascular, renal and nervous systems, as well as endocrine and pulmonary disorders.

  • Although the development of novel AR ligands has therefore been the focus of much research, so far none has been approved for clinical use, in part owing to the ubiquity of ARs and the consequent possibility of side effects. However, there has been a recent impetus towards novel clinical targets, stimulated by the discovery and elucidation of the roles of the various AR subtypes and adenosine.

  • The A1, A2A, A2B and A3 are the four known subtypes of adenosine receptors (ARs). All four subtypes are members of the superfamily of G-protein-coupled receptors, and each of these ARs has a unique pharmacological profile, tissue distribution and effector coupling.

  • Classically, AR signalling is thought to occur through inhibition or stimulation of adenylyl cyclase (also known as adenylate cyclase). However, it is now apparent that other pathways, such as phospholipase C, Ca2+ and mitogen-activated protein kinases, are also relevant.

  • Modification of adenosine has been the key strategy for discovering AR agonists and the structure–activity relationships of adenosine at ARs have been extensively probed. Highly selective agonists of the different ARs have been designed through both empirical approaches and a semi-rational approach based on molecular modelling.

Abstract

Adenosine receptors are major targets of caffeine, the most commonly consumed drug in the world. There is growing evidence that they could also be promising therapeutic targets in a wide range of conditions, including cerebral and cardiac ischaemic diseases, sleep disorders, immune and inflammatory disorders and cancer. After more than three decades of medicinal chemistry research, a considerable number of selective agonists and antagonists of adenosine receptors have been discovered, and some have been clinically evaluated, although none has yet received regulatory approval. However, recent advances in the understanding of the roles of the various adenosine receptor subtypes, and in the development of selective and potent ligands, as discussed in this review, have brought the goal of therapeutic application of adenosine receptor modulators considerably closer.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Adenosine receptor signalling pathways.
Figure 2: Adenosine receptor agonists.
Figure 3: Adenosine receptor agonists.
Figure 4: Adenosine receptor antagonists.
Figure 5: Adenosine receptor antagonists.
Figure 6: Examples of allosteric enhancers of the activity of adenosine receptor agonists.
Figure 7: Novel disease targets for selective adenosine receptor ligands.

Similar content being viewed by others

References

  1. Fredholm, B. B., IJzerman, A. P., Jacobson, K. A., Klotz, K. N. & Linden, J. International Union of Pharmacology. XXV. Nomenclature and classification of adenosine receptors. Pharmacol. Rev. 53, 527–552 (2001). A publication on AR nomenclature, structure, function and regulation by members of NC-IUPHAR subcommittee.

    CAS  PubMed  Google Scholar 

  2. Linden, J. Adenosine in tissue protection and tissue regeneration. Mol. Pharmacol. 67, 1385–1387 (2005). Summarizes four modes of adenosine's tissue protective action.

    Article  CAS  PubMed  Google Scholar 

  3. McGaraughty, S., Cowart, M., Jarvis, M. F. & Berman, R. F. Anticonvulsant and antinociceptive actions of novel adenosine kinase inhibitors. Curr. Top. Med. Chem. 5, 43–58 (2005).

    Article  CAS  PubMed  Google Scholar 

  4. Zimmermann, H. Extracellular metabolism of ATP and other nucleotides. Naunyn Schmiedebergs Arch. Pharmacol. 362, 299–309 (2000).

    Article  CAS  PubMed  Google Scholar 

  5. Pascual, O. et al. Astrocytic purinergic signalling coordinates synaptic networks. Science 310, 113–116 (2005).

    Article  CAS  PubMed  Google Scholar 

  6. Parkinson, F. E., Xiong, W. & Zamzow, C. R. Astrocytes and neurons: different roles in regulating adenosine levels. Neurol. Res. 27, 153–160 (2005).

    Article  CAS  PubMed  Google Scholar 

  7. Gao, Z. G., Kim, S. K., IJzerman, A. P. & Jacobson, K. A. Allosteric modulation of the adenosine family of receptors. Mini Rev. Med. Chem. 5, 545–553 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. van Calker, D., Muller, M. & Hamprecht, B. Adenosine regulates via two different types of receptors, the accumulation of cyclic AMP in cultured brain cells. J. Neurochem. 33, 999–1005 (1979).

    Article  CAS  PubMed  Google Scholar 

  9. Londos, C., Cooper, D. M. & Wolff, J. Subclasses of external adenosine receptors. Proc. Natl Acad. Sci. USA 77, 2551–2554 (1980).

    Article  CAS  PubMed  Google Scholar 

  10. Tawfik, H. E., Schnermann, J., Oldenburg, P. J. & Mustafa, S. J. Role of A1 adenosine receptors in the regulation of vascular tone. Am. J. Physiol. Heart Circ. Physiol. 288, H1411–H1416 (2005).

    Article  CAS  PubMed  Google Scholar 

  11. Rogel, A., Bromberg, Y., Sperling, O. & Zoref-Shani, E. Phospholipase C is involved in the adenosine-activated signal transduction pathway conferring protection against iodoacetic acid-induced injury in primary rat neuronal cultures. Neurosci. Lett. 373, 218–221 (2005).

    Article  CAS  PubMed  Google Scholar 

  12. Belardinelli, L., Shryock, J. C., Song, Y., Wang, D. & Srinivas, M. Ionic basis of the electrophysiological actions of adenosine on cardiomyocytes. FASEB J. 9, 359–365 (1995).

    Article  CAS  PubMed  Google Scholar 

  13. Reid, E. A. et al. In vivo adenosine receptor preconditioning reduces myocardial infarct size via subcellular ERK signalling. Am. J. Physiol. Heart Circ. Physiol. 288, H2253–H2259 (2005).

    Article  CAS  PubMed  Google Scholar 

  14. Kull, B., Svenningsson, P. & Fredholm, B. B. Adenosine A2A receptors are colocalized with and activate Golf in rat striatum. Mol. Pharmacol. 58, 771–777 (2000).

    Article  CAS  PubMed  Google Scholar 

  15. Fresco, P., Diniz, C. & Goncalves, J. Facilitation of noradrenaline release by activation of adenosine A2A receptors triggers both phospholipase C and adenylate cyclase pathways in rat tail artery. Cardiovasc. Res. 63, 739–746 (2004).

    Article  CAS  PubMed  Google Scholar 

  16. Offermanns, S. & Simon, M. I. Gα 15 and Gα 16 couple a wide variety of receptors to phospholipase C. J. Biol. Chem. 270, 15175–15180 (1995).

    Article  CAS  PubMed  Google Scholar 

  17. Daly, J. W., Butts-Lamb, P. & Padgett, W. Subclasses of adenosine receptors in the central nervous system: interaction with caffeine and related methylxanthines. Cell. Mol. Neurobiol. 3, 69–80 (1983).

    Article  CAS  PubMed  Google Scholar 

  18. Brackett, L. E. & Daly, J. W. Functional characterization of the A2B adenosine receptor in NIH 3T3 fibroblasts. Biochem. Pharmacol. 47, 801–814 (1994).

    Article  CAS  PubMed  Google Scholar 

  19. Peakman, M. C. & Hill, S. J. Adenosine A2B-receptor-mediated cyclic AMP accumulation in primary rat astrocytes. Br. J. Pharmacol. 111, 191–198 (1994).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Feoktistov, I. & Biaggioni, I. Adenosine A2B receptors evoke interleukin-8 secretion in human mast cells. An enprofylline-sensitive mechanism with implications for asthma. J. Clin. Invest. 96, 1979–1986 (1995).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Gao, Z., Chen, T., Weber, M. J. & Linden, J. A2B adenosine and P2Y2 receptors stimulate mitogen-activated protein kinase in human embryonic kidney-293 cells. Cross-talk between cyclic AMP and protein kinase C pathways. J. Biol. Chem. 274, 5972–5980 (1999).

    Article  CAS  PubMed  Google Scholar 

  22. Linden, J., Thai, T., Figler, H., Jin, X. & Robeva, A. S. Characterization of human A2B adenosine receptors: radioligand binding, western blotting, and coupling to Gq in human embryonic kidney 293 cells and HMC-1 mast cells. Mol. Pharmacol. 56, 705–713 (1999).

    CAS  PubMed  Google Scholar 

  23. Donoso, M. V., Lopez, R., Miranda, R., Briones, R. & Huidobro-Toro, J. P. A2B adenosine receptor mediates human chorionic vasoconstriction and signals through the arachidonic acid cascade. Am. J. Physiol. Heart Circ. Physiol. 288, H2439–H2449 (2005).

    Article  CAS  PubMed  Google Scholar 

  24. Zhou, Q. Y. et al. Molecular cloning and characterization of an adenosine receptor: the A3 adenosine receptor. Proc. Natl Acad. Sci. USA 89, 7432–7436 (1992).

    Article  CAS  PubMed  Google Scholar 

  25. Abbracchio, M. P. et al. G protein-dependent activation of phospholipase C by adenosine A3 receptors in rat brain. Mol. Pharmacol. 48, 1038–1045 (1995).

    CAS  PubMed  Google Scholar 

  26. Shneyvays, V. et al. Role of adenosine A1 and A3 receptors in regulation of cardiomyocyte homeostasis after mitochondrial respiratory chain injury. Am. J. Physiol. Heart Circ. Physiol. 288, H2792–H2801 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Englert, M., Quitterer, U. & Klotz, K. N. Effector coupling of stably transfected human A3 adenosine receptors in CHO cells. Biochem. Pharmacol. 64, 61–65 (2002).

    Article  CAS  PubMed  Google Scholar 

  28. Fossetta, J. et al. Pharmacological analysis of calcium responses mediated by the human A3 adenosine receptor in monocyte-derived dendritic cells and recombinant cells. Mol. Pharmacol. 63, 342–350 (2003).

    Article  CAS  PubMed  Google Scholar 

  29. Shneyvays, V., Zinman, T. & Shainberg, A. Analysis of calcium responses mediated by the A3 adenosine receptor in cultured newborn rat cardiac myocytes. Cell Calcium 36, 387–396 (2004).

    Article  CAS  PubMed  Google Scholar 

  30. Tracey, W. R., Magee, W., Masamune, H., Oleynek, J. J. & Hill, R. J. Selective activation of adenosine A3 receptors with N6-(3-chlorobenzyl)-5′-N-methylcarbox-amidoadenosine (CB-MECA) provides cardioprotection via KATP channel activation. Cardiovasc. Res. 40, 138–145 (1998).

    Article  CAS  PubMed  Google Scholar 

  31. Mozzicato, S., Joshi, B. V., Jacobson, K. A. & Liang, B. T. Role of direct RhoA-phospholipase D1 interaction in mediating adenosine-induced protection from cardiac ischemia. FASEB J. 18, 406–408 (2004).

    Article  CAS  PubMed  Google Scholar 

  32. Fishman, P. et al. Evidence for involvement of Wnt signalling pathway in IB-MECA mediated suppression of melanoma cells. Oncogene 21, 4060–4064 (2002).

    Article  CAS  PubMed  Google Scholar 

  33. Schulte, G. & Fredholm, B. B. Signalling pathway from the human adenosine A3 receptor expressed in Chinese hamster ovary cells to the extracellular signal-regulated kinase 1/2. Mol. Pharmacol. 62, 1137–1146 (2002).

    Article  CAS  PubMed  Google Scholar 

  34. Schulte, G. & Fredholm, B. B. Signalling from adenosine receptors to mitogen-activated protein kinases. Cell Signal. 15, 813–827 (2003). Reports that each of the four ARs can activate one or more of the MAPKs by substantially different mechanisms.

    Article  CAS  PubMed  Google Scholar 

  35. Merighi, S. et al. A3 adenosine receptor activation inhibits cell proliferation via phosphatidylinositol 3-kinase (PI3K)/AKT-dependent inhibition of the extracellular signal-regulated kinase (ERK)1/2 phosphorylation in A375 human melanoma cells. J. Biol. Chem. 280, 19516–19526 (2005).

    Article  CAS  PubMed  Google Scholar 

  36. Olah, M. E. & Stiles, G. L. The role of receptor structure in determining adenosine receptor activity. Pharmacol. Ther. 85, 55–75 (2000).

    Article  CAS  PubMed  Google Scholar 

  37. Yan, L., Burbiel, J. C., Maass, A. & Müller, C. E. Adenosine receptor agonists: from basic medicinal chemistry to clinical development. Expert Opin. Emerging Drugs 8, 537–576 (2003).

    Article  CAS  Google Scholar 

  38. Kim, S. K. et al. Modelling the adenosine receptors: Comparison of binding domains of A2A agonist and antagonist. J. Med. Chem. 46, 4847–4859 (2003).

    Article  CAS  PubMed  Google Scholar 

  39. Tchilibon, S. et al. (N)-Methanocarba-2,N6-disubstituted adenine nucleosides as highly potent and selective A3 adenosine receptor agonists. J. Med. Chem. 48, 1745–1758 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Moro, S., Gao, Z. G., Jacobson, K. A. & Spalluto, G. Progress in pursuit of therapeutic adenosine receptor antagonists. Med. Res. Rev. 26, 131–159 (2006). Summary of the most recent progress in developing new therapeutic AR antagonists.

    Article  CAS  PubMed  Google Scholar 

  41. Moro, S., Bacillieri, M., Cacciari, B. & Spalluto, G. Autocorrelation of molecular electrostatic potential surface properties combined with partial least squares analysis as new strategy for the prediction of the activity of human A3 adenosine receptor antagonists. J. Med. Chem. 48, 5698–5704 (2005).

    Article  CAS  PubMed  Google Scholar 

  42. Gao, Z. G. et al. Structural determinants of A3 adenosine receptor activation: Nucleoside ligands at the agonist/antagonist boundary. J. Med. Chem. 45, 4471–4484 (2002).

    Article  CAS  PubMed  Google Scholar 

  43. Gao, Z. G., Blaustein, J., Gross, A. S., Melman, N. & Jacobson, K. A. N6–Substituted adenosine derivatives: selectivity, efficacy, and species differences at A3 adenosine receptors, Biochem. Pharmacol. 65, 1675–1684 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Martin, P. L., Wysocki, R. J. Jr, Barrett, R. J., May, J. M. & Linden, J. Characterization of 8-(N-methylisopropyl)amino-N6-(5′-endohydroxy- endonorbornyl)-9-methyladenine (WRC-0571), a highly potent and selective, non-xanthine antagonist of A1 adenosine receptors. J. Pharmacol. Exp. Ther. 276, 490–499 (1996).

    CAS  PubMed  Google Scholar 

  45. Rieger, J. M., Brown, M. L., Sullivan, G. W., Linden, J. & MacDonald, T. L. Design, synthesis, and evaluation of novel adenosine A2A receptor agonists. J. Med. Chem. 44, 531–539 (2001).

    Article  CAS  PubMed  Google Scholar 

  46. Bridges, A. J. et al. N6-[2-(3, 5-dimethoxyphenyl)-2-(2-methylphenyl)ethyl]adenosine and its uronamide derivatives. Novel adenosine agonists with both high affinity and high selectivity for the adenosine A2 receptor. J. Med. Chem. 31, 1282–1285 (1988).

    Article  CAS  PubMed  Google Scholar 

  47. Palmer, T. M., Poucher, S. M., Jacobson, K. A. & Stiles, G. L. 125I-4-(2-[7-Amino-2-{furyl}{1,2,4}tri-azolo{2,3-a}{1,3,5}triazin-5-ylaminoethyl)phenol (125I-ZM241385), a high affinity antagonist radioligand selective for the A2A adenosine receptor. Mol. Pharmacol. 48, 970–974 (1996).

    Google Scholar 

  48. Baraldi, P. G. et al. Design, synthesis, and biological evaluation of a second generation of pyrazolo[4,3-e]1, 2,4-triazolo[1,5-c]pyrimidines as potent and selective A2A adenosine receptor antagonists. J. Med. Chem. 41, 2126–2133 (1998).

    Article  CAS  PubMed  Google Scholar 

  49. Ji, X. D. & Jacobson, K. A. [3H]-ZM241385 as a radioligand at recombinant human A2B adenosine receptors. Drug Des. Discov. 16, 217–226 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  50. Kase, H. et al. 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, S97–S100 (2003).

    Article  CAS  PubMed  Google Scholar 

  51. Volpini, R., Costanzi, S., Vittori, S., Cristalli, G. & Klotz, K. N. Medicinal chemistry and pharmacology of A2B adenosine receptors. Curr. Top. Med. Chem. 3, 427–443 (2003).

    Article  CAS  PubMed  Google Scholar 

  52. Beukers, M. W. et al. New, non-adenosine, high-potency agonists for the human adenosine A2B receptor with an improved selectivity profile compared to the reference agonist N-ethylcarboxamido-adenosine. J. Med. Chem. 47, 3707–3709 (2004). The first report of non-nucleoside agonists for the human A 2B AR, with one of those compounds showing potency of about 10 nM.

    Article  CAS  PubMed  Google Scholar 

  53. Ji, X., Kim, Y. C., Ahern, D. G., Linden, J. & Jacobson, K. A. [3H]MRS 1754, a selective antagonist radioligand for A2B adenosine receptors. Biochem. Pharmacol. 61, 657–663 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Gessi, S. et al. Expression, pharmacological profile, and functional coupling of A2B receptors in a recombinant system and in peripheral blood cells using a novel selective antagonist radioligand, [3H]MRE 2029-F20. Mol. Pharmacol. 67, 2137–2147 (2005).

    Article  CAS  PubMed  Google Scholar 

  55. Stewart, M. et al. [3H]OSIP339391, a selective, novel, and high affinity antagonist radioligand for adenosine A2B receptors. Biochem. Pharmacol. 68, 305–312 (2004).

    Article  CAS  PubMed  Google Scholar 

  56. Jacobson, K. A. A3 adenosine receptors: novel ligands and paradoxical effects. Trends Pharmacol. Sci. 19, 184–191 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Olah, M. E., Gallo-Rodriguez, C., Jacobson, K. A. & Stiles, G. L. 125I-4-Aminobenzyl-5′-N-methylcarboxamidoadenosine, a high affinity radioligand for the rat A3 adenosine receptor. Mol. Pharmacol. 45, 978–982 (1994).

    CAS  PubMed  PubMed Central  Google Scholar 

  58. Jeong, L. S. et al. N6–Substituted D-4′-thioadenosine-5′-methyluronamides: potent and selective agonists at the human A3 adenosine receptor. J. Med. Chem. 46, 3775–3777 (2003).

    Article  CAS  PubMed  Google Scholar 

  59. Linden, J. Cloned adenosine A3 receptors: pharmacological properties, species differences and receptor functions. Trends Pharmacol. Sci. 15, 298–306 (1994).

    Article  CAS  PubMed  Google Scholar 

  60. Yang, H. et al. The cross-species A3 adenosine-receptor antagonist MRS 1292 inhibits adenosine-triggered human nonpigmented ciliary epithelial cell fluid release and reduces mouse intraocular pressure. Curr. Eye Res. 30, 747–754 (2005). Application of the first rationally designed, cross-species, nucleoside antagonist in an animal model for antiglaucoma effects.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Müller, C. E., Diekmann, M., Thorand, M. & Ozola, V. [3H]8-Ethyl-4-methyl-2-phenyl-(8R)-4,5,7,8-tetrahydro-1H-imidazo[2,1-i]-purin-5-one ([3H]PSB-11), a novel high-affinity antagonist radioligand for human A3 adenosine receptors. Bioorg. Med. Chem. Lett. 12, 501–503 (2002).

    Article  PubMed  Google Scholar 

  62. Perreira, M. et al. 'Reversine' and its 2-substituted adenine derivatives as potent and selective A3 adenosine receptor antagonists. J. Med. Chem. 48, 4910–4918 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Zablocki, J. A., Wu, L., Shryock, J. & Belardinelli, L. Partial A1 adenosine receptor agonists from a molecular perspective and their potential use as chronic ventricular rate control agents during atrial fibrillation (AF). Curr. Top. Med. Chem. 4, 839–854 (2004).

    Article  CAS  PubMed  Google Scholar 

  64. Fraser, H., Gao, Z., Ozeck, M. J. & Belardinelli, L. N-[3-(R)-tetrahydrofuranyl]-6-aminopurine riboside, an A1 adenosine receptor agonist, antagonizes catecholamine-induced lipolysis without cardiovascular effects in awake rats. J. Pharmacol. Exp. Ther. 305, 225–231 (2003).

    Article  CAS  PubMed  Google Scholar 

  65. Bayes, M., Rabasseda, X. & Prous, J. R. Gateways to clinical trials. Methods Find. Exp. Clin. Pharmacol. 25, 831–855 (2003).

    CAS  PubMed  Google Scholar 

  66. Ellenbogen, K. A. et al. Trial to evaluate the management of paroxysmal supraventricular tachycardia during an electrophysiology study with tecadenoson. Circulation 111, 3202–3208 (2005). Reports that the A 1 AR agonist, Tecadenoson, terminates paroxysmal supraventricular tachycardia without the clinically significant side effects caused by stimulation of other ARs.

    Article  CAS  PubMed  Google Scholar 

  67. Wagner, H. et al. General pharmacology of SDZ WAG-994, a potent selective and orally-active adenosine A1 receptor agonist. Drug Dev. Res. 34, 276–288 (1995).

    Article  CAS  Google Scholar 

  68. Auchampach, J. A. et al. Selective activation of A3 adenosine receptors with N6-(3-iodobenzyl) adenosine-5′-N-methyluronamide protects against myocardial stunning and infarction without hemodynamic changes in conscious rabbits. Circ. Res. 80, 800–809 (1997).

    Article  CAS  PubMed  Google Scholar 

  69. Schindler, C. W. et al. Role of central and peripheral adenosine receptors in the cardiovascular responses to intraperitoneal injections of adenosine A1 and A2A subtype receptor agonists. Br. J. Pharmacol. 144, 642–650 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Schulte, G. et al. Adenosine A1 receptors are necessary for protection of the murine heart by remote, delayed adaptation to ischaemia. Acta Physiol. Scand. 182, 133–143 (2004).

    Article  CAS  PubMed  Google Scholar 

  71. Matherne, G. P., Linden, J., Byford, A. M., Gauthier, N. S. & Headrick, J. P. Transgenic A1 adenosine receptor overexpression increases myocardial resistance to ischemia. Proc. Natl Acad. Sci. USA 94, 6541–6546 (1997).

    Article  CAS  PubMed  Google Scholar 

  72. Gauthier, N. S., Headrick, J. P. & Matherne, G. P. Myocardial function in the working mouse heart overexpressing cardiac A1 adenosine receptors. J. Mol. Cell. Cardiol. 30, 187–193 (1998).

    Article  CAS  PubMed  Google Scholar 

  73. Yang, Z. et al. Cardiac overexpression of A1-adenosine receptor protects intact mice against myocardial infarction. Am. J. Physiol. Heart Circ. Physiol. 282, H949–H955 (2002).

    Article  CAS  PubMed  Google Scholar 

  74. Headrick, J. P., Gauthier, N. S., Morrison, R. & Matherne, G. P. Cardioprotection by K(ATP) channels in wild-type hearts and hearts overexpressing A1-adenosine receptors. Am. J. Physiol. Heart Circ. Physiol. 279, H1690–H1697 (2000).

    Article  CAS  PubMed  Google Scholar 

  75. Cerniway, R. J., Yang, Z., Jacobson, M. A., Linden, J. & Matherne, G. P. Targeted deletion of A3 adenosine receptors improves tolerance to ischemia-reperfusion injury in mouse myocardium. Am. J. Physiol. Heart Circ. Physiol. 281, H1751–H1758 (2001).

    Article  CAS  PubMed  Google Scholar 

  76. Joosen, M. J., Bueters, T. J. & van Helden, H. P. Cardiovascular effects of the adenosine A1 receptor agonist N6-cyclopentyladenosine (CPA) decisive for its therapeutic efficacy in sarin poisoning. Arch. Toxicol. 78, 34–39 (2004).

    Article  CAS  PubMed  Google Scholar 

  77. Reichelt, M. E. et al. Genetic deletion of the A1 adenosine receptor limits myocardial ischemic tolerance. Circ. Res. 96, 363–367 (2005).

    Article  CAS  PubMed  Google Scholar 

  78. Tracey, W. R. et al. Novel N6-substituted adenosine 5′-N-methyluronamides with high selectivity for human adenosine A3 receptors reduce ischemic myocardial injury. Am. J. Physiol. Heart Circ. Physiol. 285, H2780–H2787 (2003).

    Article  CAS  PubMed  Google Scholar 

  79. Cross, H. R., Murphy, E., Black, R. G., Auchampach, J. & Steenbergen, C. Overexpression of A3 adenosine receptors decreases heart rate, preserves energetics, and protects ischemic hearts. Am. J. Physiol. Heart Circ. Physiol. 283, H1562–H1568 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Black, R. G. et al. Gene dosage-dependent effects of cardiac-specific overexpression of the A3 adenosine receptor. Circ. Res. 91, 165–172 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. Guo, Y. et al. Targeted deletion of the A3 adenosine receptor confers resistance to myocardial ischemic injury and does not prevent early preconditioning. J. Mol. Cell Cardiol. 33, 825–830 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Harrison, G. J. et al. Effects of A3 adenosine receptor activation and gene knock-out in ischemic-reperfused mouse heart. Cardiovasc. Res. 53, 147–155 (2002).

    Article  CAS  PubMed  Google Scholar 

  83. Yang, Z. et al. Infarct sparing effect of A2A-adenosine receptor activation is due primarily to its actions on lymphocytes. Circulation 111, 2190–2197 (2005).

    Article  CAS  PubMed  Google Scholar 

  84. Gerlai, R. Gene-targeting studies of mammalian behavior: is it the mutation or the background genotype? Trends Neurosci. 19, 177–181 (1996).

    Article  CAS  PubMed  Google Scholar 

  85. De Jonge, R., Out, M., Maas, W. J. & De Jong, J. W. Preconditioning of rat hearts by adenosine A1 or A3 receptor activation. Eur. J. Pharmacol. 441, 165–172 (2002).

    Article  CAS  PubMed  Google Scholar 

  86. Wang, J. et al. Dual activation of adenosine A1 and A3 receptors mediates preconditioning of isolated cardiac myocytes. Eur. J. Pharmacol. 320, 241–248 (1997).

    Article  CAS  PubMed  Google Scholar 

  87. Shneyvays, V., Mamedova, L., Zinman, T., Jacobson, K. A. & Shainberg, A. Activation of A3 adenosine receptor protects against doxorubicin-induced cardiotoxicity. J. Mol. Cell. Cardiol. 33, 1249–1261 (2001).

    Article  CAS  PubMed  Google Scholar 

  88. Varani, K. et al. Dose and time effects of caffeine intake on human platelet adenosine A2A receptors: functional and biochemical aspects. Circulation 102, 285–289 (2000).

    Article  CAS  PubMed  Google Scholar 

  89. Hendel, R.C. et al. Initial clinical experience with regadenoson, a novel selective A2A agonist for pharmacologic stress single-photon emission computed tomography myocardial perfusion imaging. J. Am. Coll. Cardiol. 46, 2069–2075 (2005).

    Article  CAS  PubMed  Google Scholar 

  90. Barrett, R. J., Lamson, M. J., Johnson, J. & Smith, W. B. Pharmacokinetics and safety of binodenoson after intravenous dose escalation in healthy volunteers. J. Nucl. Cardiol. 12, 166–171 (2005).

    Article  PubMed  Google Scholar 

  91. Rubino, A., Ralevic, V. & Burnstock, G. The P1-purinoceptors that mediate the prejunctional inhibitory effect of adenosine on capsaicin-sensitive nonadrenergic noncholinergic neurotransmission in the rat mesenteric arterial bed are of the A1 subtype. J. Pharmacol. Exp. Ther. 267, 1100–1104 (1993).

    CAS  PubMed  Google Scholar 

  92. Szentmiklosi, A. J. et al. Adenosine receptors mediate both contractile and relaxant effects of adenosine in main pulmonary artery of guinea pigs. Naunyn. Schmiedebergs Arch. Pharmacol. 351, 417–425 (1995).

    Article  CAS  Google Scholar 

  93. Eltzschig, H. K. et al. Coordinated adenine nucleotide phosphohydrolysis and nucleoside signalling in posthypoxic endothelium: role of ectonucleotidases and adenosine A2B receptors. J. Exp. Med. 198, 783–796 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  94. Dubey, R. K., Gillespie, D. G., Shue, H. & Jackson, E. K. A2B receptors mediate antimitogenesis in vascular smooth muscle cells. Hypertension 35, 267–272 (2000).

    Article  CAS  PubMed  Google Scholar 

  95. Chen, Y. et al. Functional effects of enhancing or silencing adenosine A2B receptors in cardiac fibroblasts. Am. J. Physiol. Heart Circ. Physiol. 287, H2478–H2486 (2004).

    Article  CAS  PubMed  Google Scholar 

  96. Matheson, P. J., Spain, D. A., Harris, P. D., Garrison, R. N. & Wilson, M. A. Glucose and glutamine gavage increase portal vein nitric oxide metabolite levels via adenosine A2B activation. J. Surg. Res. 84, 57–63 (1999).

    Article  CAS  PubMed  Google Scholar 

  97. Feoktistov, I. et al. Hypoxia modulates adenosine receptors in human endothelial and smooth muscle cells toward an A2B angiogenic phenotype. Hypertension 44, 649–654 (2004). Description of the angiogenic role of the A 2B AR under hypoxic conditions.

    Article  CAS  PubMed  Google Scholar 

  98. Tilley, S. L., Wagoner, V. A., Salvatore, C. A., Jacobson, M. A. & Koller, B. H. Adenosine and inosine increase cutaneous vasopermeability by activating A3 receptors on mast cells. J. Clin. Invest. 105, 361–367 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  99. Zhao, Z., Makaritsis, K., Francis, C. E., Gavras, H. & Ravid, K. A role for the A3 adenosine receptor in determining tissue levels of cAMP and blood pressure: studies in knock-out mice. Biochim. Biophys. Acta 1500, 280–290 (2000).

    Article  CAS  PubMed  Google Scholar 

  100. Talukder, M. A. et al. Targeted deletion of adenosine A3 receptors augments adenosine-induced coronary flow in isolated mouse heart. Am. J. Physiol. Heart Circ. Physiol. 282, H2183–H2189 (2002).

    Article  CAS  PubMed  Google Scholar 

  101. Jones, M. R. et al. A3 adenosine receptor deficiency does not influence atherogenesis. J. Cell Biochem. 92, 1034–1043 (2004).

    Article  CAS  PubMed  Google Scholar 

  102. Solinas, M. et al. Involvement of adenosine A1 receptors in the discriminative-stimulus effects of caffeine in rats. Psychopharmacology (Berl.) 179, 576–586 (2005).

    Article  CAS  Google Scholar 

  103. Ledent, C. et al. Aggressiveness, hypoalgesia and high blood pressure in mice lacking the adenosine A2A receptor. Nature 388, 674–678 (1997). The first demonstration of A 2A AR-mediated effects, such as pain, aggregation of platelets, hypertension and caffeine's stimulant effect, by using a receptor-knockout model.

    Article  CAS  Google Scholar 

  104. Fredholm, B. B., Chen, J. F., Masino, S. A. & Vaugeois, J. M. Actions of adenosine at its receptors in the CNS: insights from knockouts and drugs. Annu. Rev. Pharmacol. Toxicol. 45, 385–412 (2005). A thoughtful overview of the roles of ARs in CNS disorders.

    Article  CAS  PubMed  Google Scholar 

  105. Huang, Z. L. et al. Adenosine A2A, but not A1, receptors mediate the arousal effect of caffeine. Nature Neurosci. 8, 858–859 (2005). The authors used both A 1 AR- and A 2A AR-knockout mice to show that the A 2A AR, not the A 1 AR, is crucial in caffeine-induced wakefulness.

    Article  CAS  PubMed  Google Scholar 

  106. Satoh, S., Matsumura, H. & Hayaishi, O. Involvement of adenosine A2A receptor in sleep promotion. Eur. J. Pharmacol. 351, 155–162 (1998).

    Article  CAS  PubMed  Google Scholar 

  107. Maemoto, T. et al. Pharmacological characterization of FR194921, a new potent, selective, and orally active antagonist for central adenosine A1 receptors. J. Pharmacol. Sci. 96, 42–52 (2004).

    Article  CAS  PubMed  Google Scholar 

  108. Sawynok, J. Adenosine receptor activation and nociception. Eur. J. Pharmacol. 347, 1–11 (1998).

    Article  CAS  PubMed  Google Scholar 

  109. Johansson, B. et al. Hyperalgesia, anxiety, and decreased hypoxic neuroprotection in mice lacking the adenosine A1 receptor. Proc. Natl. Acad. Sci. USA 98, 9407–9412 (2001). Initial study of A 1 AR-mediated CNS effect by using A 1 AR-knockout mice.

    Article  CAS  PubMed  Google Scholar 

  110. Wu, W. P. et al. Increased nociceptive response in mice lacking the adenosine A1 receptor. Pain 113, 395–404 (2005).

    Article  CAS  PubMed  Google Scholar 

  111. Gordh, T., Karlsten, R. & Kristensen, J. Intervention with spinal NMDA, adenosine, and NO systems for pain modulation. Ann. Med. 27, 229–234 (1995).

    Article  CAS  PubMed  Google Scholar 

  112. Giffin, N. J. et al. Effect of the adenosine A1 receptor agonist GR79236 on trigeminal nociception with blink reflex recordings in healthy human subjects. Cephalalgia 23, 287–292 (2003).

    Article  CAS  PubMed  Google Scholar 

  113. Zambrowicz, B. P., Turner, C. A. & Sands, A. T. Predicting drug efficacy: knockouts model pipeline drugs of the pharmaceutical industry. Curr. Opin. Pharmacol. 3, 563–570 (2003).

    Article  CAS  PubMed  Google Scholar 

  114. Li, X., Conklin, D., Pan, H. L. & Eisenach, J. C. Allosteric adenosine receptor modulation reduces hypersensitivity following peripheral inflammation by a central mechanism. J. Pharmacol. Exp. Ther. 305, 950–955 (2003).

    Article  CAS  PubMed  Google Scholar 

  115. Ferre, S., von Euler, G., Johansson, B., Fredholm, B. B. & Fuxe, K. Stimulation of high-affinity adenosine A2 receptors decreases the affinity of dopamine D2 receptors in rat striatal membranes. Proc. Natl Acad. Sci. USA 88, 7238–7241 (1991).

    Article  CAS  PubMed  Google Scholar 

  116. Hillion, J. et al. Coaggregation, cointernalization, and codesensitization of adenosine A2A receptors and dopamine D2 receptors. J. Biol. Chem. 277, 18091–18097 (2002).

    Article  CAS  PubMed  Google Scholar 

  117. Svenningsson, P., Le Moine, C., Fisone, G. & Fredholm, B. B. Distribution, biochemistry and function of striatal adenosine A2A receptors. Prog. Neurobiol. 59, 355–396 (1999).

    Article  CAS  PubMed  Google Scholar 

  118. Aoyama, S., Kase, H. & Borrelli, E. Rescue of locomotor impairment in dopamine D2 receptor-deficient mice by an adenosine A2A receptor antagonist. J. Neurosci. 20, 5848–5852 (2000).

    Article  CAS  PubMed  Google Scholar 

  119. Xu, K., Bastia, E. & Schwarzschild, M. Therapeutic potential of adenosine A2A receptor antagonists in Parkinson's disease. Pharmacol. Ther. 105, 267–310 (2005).

    Article  CAS  PubMed  Google Scholar 

  120. Ross, G. W. et al. Association of coffee and caffeine intake with the risk of Parkinson disease. JAMA 283, 2674–2679 (2000).

    Article  CAS  PubMed  Google Scholar 

  121. Ascherio, A. et al. Prospective study of caffeine consumption and risk of Parkinson's disease in men and women. Ann. Neurol. 50, 56–63 (2001).

    Article  CAS  PubMed  Google Scholar 

  122. Bara-Jimenez, W. et al. Adenosine A2A receptor antagonist treatment of Parkinson's disease. Neurology 61, 293–296 (2003).

    Article  CAS  PubMed  Google Scholar 

  123. Hauser, R. A., Hubble, J. P. & Truong, D. D. Randomized trial of the adenosine A2A receptor antagonist istradefylline in advanced PD. Neurology 61, 297–303 (2003).

    Article  CAS  PubMed  Google Scholar 

  124. Weiss, S. M. et al. Discovery of nonxanthine adenosine A2A receptor antagonists for the treatment of Parkinson's disease. Neurology 61, S101–S106 (2003).

    Article  CAS  PubMed  Google Scholar 

  125. Matasi, J. J. et al. The discovery and synthesis of novel adenosine receptor A2A antagonists. Bioorg. Med. Chem. Lett. 15, 1333–1336 (2005).

    Article  CAS  PubMed  Google Scholar 

  126. Peng, H. et al. Novel bicyclic piperazine derivatives of triazolotriazine and triazolopyrimidines as highly potent and selective adenosine A2A receptor antagonists. J. Med. Chem. 47, 6218–6229 (2004).

    Article  CAS  PubMed  Google Scholar 

  127. Chen, J. F. et al. A2A adenosine receptor deficiency attenuates brain injury induced by transient focal ischemia in mice. J. Neurosci. 19, 9192–9200 (1999). Provides a genetic basis for treating PD with A 2A AR antagonists.

    Article  CAS  PubMed  Google Scholar 

  128. Monopoli, A., Lozza, G., Forlani, A., Mattavelli, A. & Ongini, E. Blockade of adenosine A2A receptors by SCH 58261 results in neuroprotective effects in cerebral ischaemia in rats. Neuroreport 9, 3955–3959 (1998).

    Article  CAS  PubMed  Google Scholar 

  129. Blum, D. et al. A dual role of adenosine A2A receptors in 3-nitropropionic acid-induced striatal lesions: implications for the neuroprotective potential of A2A antagonists. J. Neurosci. 23, 5361–5369 (2003).

    Article  CAS  PubMed  Google Scholar 

  130. Yu, L. et al. Selective inactivation or reconstitution of adenosine A2A receptors in bone marrow cells reveals their significant contribution to the development of ischemic brain injury. Nature Med. 10, 1081–1087 (2004).

    Article  CAS  PubMed  Google Scholar 

  131. Aden, U. et al. Aggravated brain damage after hypoxic ischemia in immature adenosine A2A knockout mice. Stroke 34, 739–744 (2003).

    Article  CAS  PubMed  Google Scholar 

  132. Mayne, M. et al. Adenosine A2A receptor activation reduces proinflammatory events and decreases cell death following intracerebral hemorrhage. Ann. Neurol. 49, 727–735 (2001).

    Article  CAS  PubMed  Google Scholar 

  133. Cassada, D. C. et al. Adenosine A2A agonist reduces paralysis after spinal cord ischemia: correlation with A2A receptor expression on motor neurons. Ann. Thorac. Surg. 74, 846–849 (2002).

    Article  PubMed  Google Scholar 

  134. von Lubitz, D. K. J. E. et al. Postischemic administration of adenosine amine congener (ADAC): analysis of recovery in gerbils. Eur. J. Pharmacol. 316, 171–179 (1996).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  135. Knutsen, L. J. et al. N-substituted adenosines as novel neuroprotective A1 agonists with diminished hypotensive effects. J. Med. Chem. 42, 3463–3477 (1999).

    Article  CAS  PubMed  Google Scholar 

  136. Olsson, T. et al. Deletion of the adenosine A1 receptor gene does not alter neuronal damage following ischaemia in vivo or in vitro. Eur. J. Neurosci. 20, 1197–1204 (2004).

    Article  PubMed  Google Scholar 

  137. Turner, C. P. et al. A1 adenosine receptors mediate hypoxia-induced ventriculomegaly. Proc. Natl Acad. Sci. USA 100, 11718–11722 (2003).

    Article  CAS  PubMed  Google Scholar 

  138. Stevens, B., Porta, S., Haak, L. L., Gallo, V. & Fields, R. D. Adenosine: a neuron-glial transmitter promoting myelination in the CNS in response to action potentials. Neuron 36, 855–868 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  139. Linden, J. et al. Molecular cloning and functional expression of a sheep A3 adenosine receptor with widespread tissue distribution. Mol. Pharmacol. 44, 524–532 (1993).

    CAS  PubMed  Google Scholar 

  140. Dixon, A. K., Gubitz, A. K., Sirinathsinghji, D. J., Richardson, P. J. & Freeman, T. C. Tissue distribution of adenosine receptor mRNAs in the rat. Br. J. Pharmacol. 118, 1461–1468 (1996).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  141. Zhao, Z., Yaar, R., Ladd, D., Cataldo, L. M. & Ravid, K. Overexpression of A3 adenosine receptors in smooth, cardiac, and skeletal muscle is lethal to embryos. Microvasc. Res. 63, 61–69 (2002).

    Article  CAS  PubMed  Google Scholar 

  142. Jacobson, K. A. et al. A role for central A3-adenosine receptors. Mediation of behavioral depressant effects. FEBS Lett. 336, 57–60 (1993).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  143. von Lubitz, D. K. J. E., Lin, R. C.-S., Popik, P., Carter, M. F. & Jacobson, K. A. Adenosine A3 receptor stimulation and cerebral ischemia. Eur. J. Pharmacol. 263, 59–67 (1994).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  144. Porkka-Heiskanen, T. et al. Adenosine: a mediator of the sleep-inducing effects of prolonged wakefulness. Science 276, 1265–1268 (1997). Shows that adenosine is a physiological sleep factor that mediates the somnogenic effects of prior wakefulness.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  145. Porkka-Heiskanen, T., Alanko, L., Kalinchuk, A. & Stenberg, D. Adenosine and sleep. Sleep Med. Rev. 6, 321–332 (2002).

    Article  PubMed  Google Scholar 

  146. Stenberg, D. et al. Sleep and its homeostatic regulation in mice lacking the adenosine A1 receptor. J. Sleep Res. 12, 283–290 (2003).

    Article  PubMed  Google Scholar 

  147. Urade, Y. et al. Sleep regulation in adenosine A2A receptor-deficient mice. Neurology 61, S94–S96 (2003).

    Article  CAS  PubMed  Google Scholar 

  148. Basheer, R., Strecker, R. E., Thakkar, M. M. & McCarley, R. W. Adenosine and sleep-wake regulation. Prog. Neurobiol. 73, 379–396 (2004).

    Article  CAS  PubMed  Google Scholar 

  149. Yao, L. et al. βγ dimers mediate synergy of dopamine D2 and adenosine A2 receptor-stimulated PKA signalling and regulate ethanol consumption. Cell 109, 733–743 (2002).

    Article  CAS  PubMed  Google Scholar 

  150. Mailliard, W. S. & Diamond, I. Recent advances in the neurobiology of alcoholism: the role of adenosine. Pharmacol. Ther. 101, 39–46 (2004).

    Article  CAS  PubMed  Google Scholar 

  151. Bauer, A. et al. 18F-CPFPX PET identifies changes in cerebral A1 adenosine receptor density caused by glioma invasion. J. Nucl. Med. 46, 450–454 (2005).

    CAS  PubMed  Google Scholar 

  152. Moresco, R. M. et al. In vivo imaging of adenosine A2A receptors in rat and primate brain using [11C]SCH442416. Eur. J. Nucl. Med. Mol. Imaging 32, 405–413 (2005).

    Article  CAS  PubMed  Google Scholar 

  153. El Yacoubi, M. et al. Absence of the adenosine A2A receptor or its chronic blockade decrease ethanol withdrawal-induced seizures in mice. Neuropharmacology 40, 424–432 (2001).

    Article  CAS  PubMed  Google Scholar 

  154. Lee, H. T. & Emala, C. W. Protective effects of renal ischemic preconditioning and adenosine pretreatment: role of A1 and A3 receptors. Am. J. Physiol. Renal Physiol. 278, F380–F387 (2000).

    Article  CAS  PubMed  Google Scholar 

  155. Pingle, S. C. et al. Osmotic diuretics induce adenosine A1 receptor expression and protect renal proximal tubular epithelial cells against cisplatin-mediated apoptosis. J. Biol. Chem. 279, 43157–43167 (2004).

    Article  CAS  PubMed  Google Scholar 

  156. Brown, R. et al. Abolished tubuloglomerular feedback and increased plasma renin in adenosine A1 receptor-deficient mice. Am. J. Physiol. Regul. Integr. Comp. Physiol. 281, R1362–R1367 (2001).

    CAS  PubMed  Google Scholar 

  157. Sun, D. et al. Mediation of tubuloglomerular feedback by adenosine: evidence from mice lacking adenosine A1 receptors. Proc. Natl Acad. Sci. USA 98, 9983–9988 (2001).

    Article  CAS  PubMed  Google Scholar 

  158. Lee, H. T., Xu, H., Nasr, S. H., Schnermann, J. & Emala, C. W. A1 adenosine receptor knockout mice exhibit increased renal injury following ischemia and reperfusion. Am. J. Physiol. Renal Physiol. 286, F298–F306 (2004).

    Article  CAS  PubMed  Google Scholar 

  159. Wilcox, C. S., Welch, W. J., Schreiner, G. F. & Belardinelli, L. Natriuretic and diuretic actions of a highly selective adenosine A1 receptor antagonist. J. Am. Soc. Nephrol. 10, 714–720 (1999).

    CAS  PubMed  Google Scholar 

  160. Gottlieb, S. S. et al. BG9719 (CVT-124), an A1 adenosine receptor antagonist, protects against the decline in renal function observed with diuretic therapy. Circulation 105, 1348–1353 (2002).

    Article  CAS  PubMed  Google Scholar 

  161. Auchampach, J. A. et al. Comparison of three different A1 adenosine receptor antagonists on infarct size and multiple cycle ischemic preconditioning in anesthetized dogs. J. Pharmacol. Exp. Ther. 308, 846–856 (2004).

    Article  CAS  PubMed  Google Scholar 

  162. Day, Y. J. et al. Renal protection from ischemia mediated by A2A adenosine receptors on bone marrow-derived cells. J. Clin. Invest. 112, 883–891 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  163. Okusa, M. D. et al. A2A adenosine receptor-mediated inhibition of renal injury and neutrophil adhesion. Am. J. Physiol. Renal Physiol. 279, F809–F818 (2000).

    Article  CAS  PubMed  Google Scholar 

  164. Zannikos, P. N. et al. Pharmacokinetics and safety of single intravenous infusions of the adenosine agonist, AMP 579, in patients with end-stage renal insufficiency. J. Clin. Pharmacol. 40, 745–751 (2000).

    Article  CAS  PubMed  Google Scholar 

  165. Vitzthum, H., Weiss, B., Bachleitner, W., Kramer, B. K. & Kurtz, A. Gene expression of adenosine receptors along the nephron. Kidney Int. 65, 1180–1190 (2004).

    Article  CAS  PubMed  Google Scholar 

  166. Cooper, J., Hill, S. J. & Alexander, S. P. An endogenous A2B adenosine receptor coupled to cyclic AMP generation in human embryonic kidney (HEK 293) cells. Br. J. Pharmacol. 122, 546–550 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  167. Dubey, R. K., Gillespie, D. G., Mi, Z. & Jackson, E. K. Adenosine inhibits PDGF-induced growth of human glomerular mesangial cells via A2B receptors. Hypertension 46, 628–634 (2005).

    Article  CAS  PubMed  Google Scholar 

  168. Lee, H. T. et al. A3 adenosine receptor knockout mice are protected against ischemia- and myoglobinuria-induced renal failure. Am. J. Physiol. Renal Physiol. 284, F267–F273 (2003).

    Article  CAS  PubMed  Google Scholar 

  169. Sun, C. X. et al. A protective role for the A1 adenosine receptor in adenosine-dependent pulmonary injury. J. Clin. Invest. 115, 35–43 (2005). Uses A 1 AR- and adenosine deaminase-deficient mice to show the occurrence of anti-inflammatory actions of adenosine in the lung, mediated through A 1 ARs, on macrophages.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  170. Holgate, S. T. The identification of the adenosine A2B receptor as a novel therapeutic target in asthma. Br. J. Pharmacol. 145, 1009–1015 (2005). Comprehensive description of the role of the A 2B AR in asthma, which provides a firm basis for developing A 2B AR antagonists as a new therapeutic approach to this disease.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  171. Salvatore, C. A. et al. Disruption of the A3 adenosine receptor gene in mice and its effect on stimulated inflammatory cells. J. Biol. Chem. 275, 4429–4434 (2000).

    Article  CAS  PubMed  Google Scholar 

  172. Feoktistov, I. & Biaggioni, I. Role of adenosine in asthma. Drug Dev. Res. 39, 333–336 (1996).

    Article  CAS  PubMed  Google Scholar 

  173. Ryzhov, S. et al. Adenosine-activated mast cells induce IgE synthesis by B lymphocytes: an A2B-mediated process involving Th2 cytokines IL-4 and IL-13 with implications for asthma. J. Immunol. 172, 7726–7733 (2004).

    Article  CAS  PubMed  Google Scholar 

  174. Auchampach, J. A., Jin, X., Wan, T. C., Caughey, G. H. & Linden, J. Canine mast cell adenosine receptors: cloning and expression of the A3 receptor and evidence that degranulation is mediated by the A2B receptor. Mol. Pharmacol. 52, 846–860 (1997).

    Article  CAS  PubMed  Google Scholar 

  175. Press, N. J. et al. A new orally bioavailable dual adenosine A2B/A3 receptor antagonist with therapeutic potential. Bioorg. Med. Chem. Lett. 15, 3081–3085 (2005).

    Article  CAS  PubMed  Google Scholar 

  176. Fozard, J. R., Ellis, K. M., Villela Dantas, M. F., Tigani, B. & Mazzoni, L. Effects of CGS 21680, a selective adenosine A2A receptor agonist, on allergic airways inflammation in the rat. Eur. J. Pharmacol. 438, 183–188 (2002).

    Article  CAS  PubMed  Google Scholar 

  177. Glaxo Group Ltd: WO9967263, WO9967264, WO9967265 & WO9967266. Selective A2A receptor agonists as inhibitors of cellular activation. Expert Opin. Ther. Pat. 10, 723–728 (2000).

  178. Rivo, J., Zeira, E., Galun, E. & Matot, I. Activation of A3 adenosine receptor provides lung protection against ischemia-reperfusion injury associated with reduction in apoptosis. Am. J. Transplant. 4, 1941–1948 (2004).

    Article  CAS  PubMed  Google Scholar 

  179. Sitkovsky, M. V. et al. Physiological control of immune response and inflammatory tissue damage by hypoxia-inducible factors and adenosine A2A receptors. Annu. Rev. Immunol. 22, 657–682 (2004). Comprehensive overview of the roles of A 2A ARs in immune response and inflammation-related tissue damage.

    Article  CAS  PubMed  Google Scholar 

  180. Erdmann, A. A. et al. Activation of Th1 and Tc1 cell adenosine A2A receptors directly inhibits IL-2 secretion in vitro and IL-2 driven expansion in vivo. Blood 105, 4707–4714 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  181. Lappas, C. M., Rieger, J. M. & Linden, J. A2A adenosine receptor induction inhibits IFN- production in murine CD4+ T cells. J. Immunol. 174, 1073–1080 (2005).

    Article  CAS  PubMed  Google Scholar 

  182. Ohta, A. & Sitkovsky, M. Role of G-protein-coupled adenosine receptors in downregulation of inflammation and protection from tissue damage. Nature 414, 916–920 (2001). Describes that A 2A ARs are crucially involved in the limitation and termination of inflammation. No other mechanism for inflammation could compensate fully for the loss of A 2A ARs on immune cells.

    Article  CAS  PubMed  Google Scholar 

  183. Kirkpatrick, P. Putting the brake on inflammation. Nature Rev. Drug Disc. 1, 99 (2002).

    Article  CAS  Google Scholar 

  184. Montesinos, M. C. et al. Adenosine A2A or A3 receptors are required for inhibition of inflammation by methotrexate and its analog MX-68. Arthritis Rheum. 48, 240–247 (2003).

    Article  CAS  PubMed  Google Scholar 

  185. Day, Y. J. et al. Protection from ischemic liver injury by activation of A2A adenosine receptors during reperfusion: inhibition of chemokine induction. Am. J. Physiol. Gastrointest. Liver Physiol. 286, G285–G293 (2004).

    Article  CAS  PubMed  Google Scholar 

  186. Sullivan, G. W., Fang, G., Linden, J. & Scheld, W. M. A2A adenosine receptor activation improves survival in mouse models of endotoxemia and sepsis. J. Infect. Dis. 189, 1897–1904 (2004).

    Article  CAS  PubMed  Google Scholar 

  187. Odashima, M. et al. Activation of A2A adenosine receptor attenuates intestinal inflammation in animal models of inflammatory bowel disease. Gastroenterology 129, 26–33 (2005).

    Article  CAS  PubMed  Google Scholar 

  188. Peirce, S. M., Skalak, T. C., Rieger, J. M., Macdonald, T. L. & Linden, J. Selective A2A adenosine receptor activation reduces skin pressure ulcer formation and inflammation. Am. J. Physiol. Heart Circ. Physiol. 281, H67–H74 (2001).

    Article  CAS  PubMed  Google Scholar 

  189. Montesinos, M. C. et al. Wound healing is accelerated by agonists of adenosine A2 (Gαs-linked) receptors. J. Exp. Med. 186, 1615–1620 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  190. Ramkumar, V., Stiles, G. L., Beaven, M. A. & Ali, H. The A3 adenosine receptor is the unique adenosine receptor which facilitates release of allergic mediators in mast cells. J. Biol. Chem. 268, 16887–16890 (1993).

    CAS  PubMed  Google Scholar 

  191. Haskó, G. & Cronstein, B. N. Adenosine: an endogenous regulator of innate immunity. Trends Immunol. 25, 33–39 (2004). Summary of adenosine's promotion of a self-limiting, healthy immune response in endothelial cells, neutrophils and mast cells.

    Article  CAS  PubMed  Google Scholar 

  192. Baharav, E. et al. Antiinflammatory effect of A3 adenosine receptor agonists in murine autoimmune arthritis models. J. Rheumatol. 32, 469–476 (2005).

    CAS  PubMed  Google Scholar 

  193. Dong, Q., Ginsberg, H. N. & Erlanger, B. F. Overexpression of the A1 adenosine receptor in adipose tissue protects mice from obesity-related insulin resistance. Diabetes Obes. Metab. 3, 360–366 (2001).

    Article  CAS  PubMed  Google Scholar 

  194. Harada, H. et al. 2-Alkynyl-8-aryl-9-methyladenines as novel adenosine receptor antagonists: their synthesis and structure-activity relationships toward hepatic glucose production induced via agonism of the A2B receptor. J. Med. Chem. 44, 170–179 (2001).

    Article  CAS  PubMed  Google Scholar 

  195. Kohno, Y., Sei, Y., Koshiba, M., Kim, H. O. & Jacobson, K. A. Induction of apoptosis in HL-60 human promyelocytic leukemia cells by adenosine A3 receptor agonists. Biochem. Biophys. Res. Commun. 219, 904–910 (1996).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  196. Kim, S. G. et al. p53-Independent induction of Fas and apoptosis in leukemic cells by an adenosine derivative, Cl-IB-MECA. Biochem. Pharmacol. 63, 871–880 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  197. Gao, Z., Li, B. S., Day, Y. J. & Linden, J. A3 adenosine receptor activation triggers phosphorylation of protein kinase B and protects rat basophilic leukemia 2H3 mast cells from apoptosis. Mol. Pharmacol. 59, 76–82 (2001).

    Article  CAS  PubMed  Google Scholar 

  198. Neary, J. T., McCarthy, M., Kang, Y. & Zuniga, S. Mitogenic signalling from P1 and P2 purinergic receptors to mitogen-activated protein kinase in human fetal astrocyte cultures. Neurosci. Lett. 242, 159–162 (1998).

    Article  CAS  PubMed  Google Scholar 

  199. Merighi, S. et al. Adenosine receptors as mediators of both cell proliferation and cell death of cultured human melanoma cells. J. Invest. Dermatol. 119, 923–933 (2002).

    Article  CAS  PubMed  Google Scholar 

  200. Fishman, P., Bar-Yehuda, S., Madi, L. & Cohn, I. A3 adenosine receptor as a target for cancer therapy. Anticancer Drugs 13, 437–443 (2002).

    Article  CAS  PubMed  Google Scholar 

  201. Madi, L. et al. The A3 adenosine receptor is highly expressed in tumor versus normal cells: potential target for tumor growth inhibition. Clin. Cancer Res. 10, 4472–4479 (2004). Shows that colon and breast carcinoma tissues have higher A 3 AR expression in the tumour versus adjacent non-neoplastic tissue or normal tissue, which provided a basis for the use of A 3 AR agonists in cancer therapy.

    Article  CAS  PubMed  Google Scholar 

  202. Lu, J., Pierron, A. & Ravid, K. An adenosine analogue, IB-MECA, down-regulates estrogen receptor alpha and suppresses human breast cancer cell proliferation. Cancer Res. 63, 6413–6423 (2003).

    CAS  PubMed  Google Scholar 

  203. Avila, M. Y., Stone, R. A. & Civan, M. M. Knockout of A3 adenosine receptors reduces mouse intraocular pressure. Invest. Ophthalmol. Vis. Sci. 43, 3021–3026 (2002).

    PubMed  Google Scholar 

  204. Okamura, T. et al. Structure-activity relationships of adenosine A3 receptor ligands: new potential therapy for the treatment of glaucoma. Bioorg. Med. Chem. Lett. 14, 3775–3779 (2004).

    Article  CAS  PubMed  Google Scholar 

  205. Jacobson, K. A. et al. Neoceptor concept based on molecular complementarity in GPCRs: a mutant adenosine A3 receptor with selectively enhanced affinity for amine-modified nucleosides, J. Med. Chem. 44, 4125–4136 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  206. Jacobson, K. A. et al. A neoceptor approach to unraveling microscopic interactions between the human A2A adenosine receptor and its agonists. Chem. Biol. 12, 237–247 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  207. Klotz, K. N. et al. Comparative pharmacology of human adenosine receptor subtypes — characterization of stably transfected receptors in CHO cells. Naunyn Schmiedebergs Arch. Pharmacol. 357, 1–9 (1998).

    CAS  Google Scholar 

  208. Palle, V. P. et al. Structure-affinity relationships of the affinity of 2-pyrazolyl adenosine analogues for the adenosine A2A receptor. Bioorg. Med. Chem. Lett. 12, 2935–2939 (2002).

    Article  CAS  PubMed  Google Scholar 

  209. Gao, Z. G. et al. Orthogonal activation of the reengineered A3 adenosine receptor (neoceptor) using tailored nucleoside agonists. J. Med. Chem (in the press).

Download references

Author information

Authors and Affiliations

  1. Molecular Recognition Section, Laboratory of Bioorganic Chemistry, National Institute of Diabetes, Digestive and Kidney Diseases, National Institutes of Health, Bethesda, 20892-0810, Maryland, USA

    Kenneth A. Jacobson & Zhan-Guo Gao

Authors
  1. Kenneth A. Jacobson
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Zhan-Guo Gao
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Kenneth A. Jacobson.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Related links

Related links

DATABASES

OMIM

Huntington's disease

Parkinson's disease

Glossary

Angiogenesis

The growth of new blood vessels — for example, in pathology, the generation of a blood supply to a tumour.

Allosteric site

A modulatory binding site on a receptor that is topographically distinct from the agonist binding site.

Pertussis toxin

A compound that inhibits the guanine nucleotide binding proteins Gi and Go via ADP-ribosylation.

Bradycardiac effect

An arrhythmia typified by an abnormally slow heart rate.

Mast cell

A type of leukocyte that has large secretory granules that contain histamine and various protein mediators.

Photoisomerization

A conversion between structural isomers caused by light-induced excitation.

Paroxysmal supraventricular tachycardia

(PSVT). A regular, abnormally fast heart beat caused by rapid firing of electrical impulses from a focus above the AV (atrioventricular) node.

Atrial fibrillation

A condition in which disorganized electrical conduction in the atrial walls results in ineffective pumping of blood into the ventricle and an irregular heart rhythm.

Dromotropic

Refers to velocity of AV nodal conduction in the heart.

Discriminative stimulus

In instrumental conditioning, the external stimulus that signals a particular relationship between the instrumental response and the reinforcer.

Somnogenic

Sleep-inducing.

TH2 cytokines

Cytokines such as interleukin (IL)-3, -4, -5, -6, -10 and -12 secreted by TH2 helper T lymphocytes to control various aspects of the antibody response.

Bioavailability

The fraction or percentage of an administered drug or other substance that becomes available to the target tissue after administration.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Jacobson, K., Gao, ZG. Adenosine receptors as therapeutic targets. Nat Rev Drug Discov 5, 247–264 (2006). https://doi.org/10.1038/nrd1983

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1038/nrd1983

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing