Adenosine Receptors

An Historical Perspective
  • Michael Williams
Part of the The Receptors book series (REC)


It is now 60 years since Drury and Szent-Györgyi (1929) found that adenosine produced profound hypotension and bradycardia as well as affecting kidney function in mammals. At a time when the thiazide diuretics, β-adrenergic receptor antagonists, and angiotensin converting enzyme (ACE) inhibitors were unknown, the potential of the nucleoside as an antihypertensive agent was attractive, and con sequently, adenosine was rapidly evaluated in man (Honey et al., 1930; Jezer et al., 1933; Drury, 1936) with disappointing results because of the lability of the natural nucleoside. Accordingly, the purine was felt to have limited usefulness as an antihypertensive agent, and it was not until the 1950s that the effects of adenosine on mammalian cellular function were again evaluated (Green and Stoner, 1950; Feldberg and Sherwood, 1953; Winbury et al.,1953; Wolf and Berne, 1956). The hypotensive actions of adenosine were reconfirmed, as was the ability of the purine to modulate pulmonary and CNS function.


Adenosine Receptor Adenosine Deaminase Adenosine Antagonist Purine Receptor Adenosine Receptor Activation 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. Arch, J. R. S. and Newsholme, E. A. (1978) The control of the metabolism and the hormonal role of adenosine. Essays Biochem. 14, 82–123.PubMedGoogle Scholar
  2. Bazil, C. W. and Minneman, K. P. (1986) An investigation of the low intrinsic activity of adenosine and its analogs at low affinity (A2) adenosine receptors in rat cerebral cortex. J. Neurochem. 47, 547–553.PubMedCrossRefGoogle Scholar
  3. Bellardinelli, L., West, A., Crampton, R., and Berne, R. M. (1983) Chronotropic and dromotropic effects of adenosine, in Regulatory Function of Adenosine ( Berne, R. M., Rall, T. W., and Rubio, R., eds.), Nijhoff, Boston, pp 377–398.Google Scholar
  4. Berne, R. M. (1963) Cardiac nucleotides in hypoxia—possible role in regulation of coronary flow. J. Physiol. (Lond.) 204, 317–322.Google Scholar
  5. Berne, R. M. (1985) Criteria for the involvement of adenosine in the regulation of blood flow, in Methods in Pharmacology vol. 6 Methods Used in Adenosine Research ( Paton, D. M., ed.) Plenum, New York, pp. 331–336.Google Scholar
  6. Berne, R. M., Rubio, R., and Curnish, R. R. (1974) Release of adenosine from ischemic brain: Effect on cerebral vascular resistance and incorporation into cerebral adenine nucleotides. Circ. Res. 35, 262–271.Google Scholar
  7. Berne, R. M., Gidday, J. M., Hill, H. E., Curnish, R. R., and Rubio, R. (1987) Adenosine in the local regulation of blood flow: Some controversies, in Topics and Perspectives in Adenosine Research ( Gerlach, E. and Becker, B. F., eds.), Springer-Verlag, Berlin, pp. 395–405.Google Scholar
  8. Braas, K. M., Newby, A. C., Wilson, V. S., and Snyder, S. H. (1986) Adenosine containing neurons in the brain localized by immunocytochemistry. J. Neurosci. 6, 1952–1961.PubMedGoogle Scholar
  9. Bruns, R. F., Lu, G., and Pugsley, T. A. (1986) Characterization of the A2 adenosine receptor labeled by [3H]NECA in rat striatal membranes. Mol. Pharmacol. 29, 331–346.PubMedGoogle Scholar
  10. Bruns, R. F., Lu, G. H., and Pugsley, T. A. (1987a) Adenosine receptor subtypes, in Topics and Perspectives in Adenosine Research ( Gerlach, E. and Becker, B. F., eds.), Springer-Verlag, Berlin, pp. 59–73.Google Scholar
  11. Bruns, R. F., Fergus, J. H., Badger, E. W., Bristol, J. A., Santay, L. A., and Hays, S. J. (1987b) PD115,199: an antagonist ligand for A2 receptors. Naunyn Schmiedebergs Arch. Pharmacol. 335, 64–69.CrossRefGoogle Scholar
  12. Burnstock, G. (1972) Purinergic nerves. Pharmacol. Rev. 24, 509–581.PubMedGoogle Scholar
  13. Burnstock, G. (1976) Purinergic receptors. J. Theor. Biol. 62, 491–503.PubMedCrossRefGoogle Scholar
  14. Bumstock, G. (1978) A basis for distinguishing two types of purinergic receptor, in Cell Membrane Receptors for Drugs and Hormones ( Bolls, L. and Straub, R. W., eds.) Raven, New York, pp. 107–118.Google Scholar
  15. Bumstock, G. and Kennedy, C. (1985) Is there a basis for distinguishing two types of PZ purinoceptor? Gen. Pharmacol. 16, 433–440.CrossRefGoogle Scholar
  16. Daly, J. W., Butts-Lamb, P., and Padgett, W. (1983) Subclasses of adenosine receptors in the central nervous system: Interaction with caffeine and related methylxanthines. Cell. Mol. Neurobiol. 3, 69–80.PubMedCrossRefGoogle Scholar
  17. Daly, J. W., Honig, O., Padgett, W. L., Shamim, W. T., Jacobson, K. A., and Ukena, D. (1988) Non-xanthine heterocycles: Activity as antagonists of Al and A2 receptors. Biochem. Pharmacol. 37, 655–664.PubMedCrossRefGoogle Scholar
  18. DiMarco, J. P., Sellers, T. D., Berne, R. M., West, G. A., and Bellardinelli, L. (1983) Adenosine: Electrophysiologic effects and therapeutic use for terminating paroxysmal supraventricular tachycardia. Circulation 68, 1254–1263.PubMedCrossRefGoogle Scholar
  19. Dragunow, M. (1988) Purinergic mechanisms in eplilepsy. Prog. Neurobiol. 31, 85–107.PubMedCrossRefGoogle Scholar
  20. Dragunow, M., Goodard, G. V., and Laverty, R. (1985) Is adenosine an endogenous anticonvulsant? Epilepsia 26, 480–487.PubMedCrossRefGoogle Scholar
  21. Drury, A. N. (1936) Physiological activity of nucleic acid and its derivatives. Physiol. Rev. 16, 292–325.Google Scholar
  22. Drury, A. N. and Szent-Györgyi, A. (1929) The physiological action of adenine compounds with especial reference to their action on the mammalian heart. J. Physiol. (Lond.) 68, 214–237.Google Scholar
  23. Engler, R. (1987) Consequences of activation and adenosine-mediated inhibition of granulocytes during myocardial ischemia. Fed. Proc. 46, 2407–2412.PubMedGoogle Scholar
  24. Evans, B. E., Riffle, K. E., Bock, M. G., DiPardo, R. M., Freidinger, R. M., Whitter, W. L., Lundell, G. F., Veber, D.F., Anderson, P. S., Chang, R. S. L., Lotti, V. L., Cerino, D. J., Chen, T. B., Kling, P. J., Kunkel, K. A., Springer, J. P., and Hirshfield, J. (1988) Methods for drug discovery: Development of potent, selective, orally effective cholecystokinin antagonists. J. Med. Chem. 31, 2235–2246.PubMedCrossRefGoogle Scholar
  25. Fedan, J. S., Hogaboom, G. K., O’Donnell, J. P., Jeng, C. J., and Guillory, G. (1985) Interaction of [3H]ANAPP3 with PZ purinergic receptors in the smooth muscle of of the isolated guinea pig vas deferens. Eur. J. Pharmacol. 108, 49–61.PubMedCrossRefGoogle Scholar
  26. Feldberg, W. and Sherwood, S. L. (1954) Injections of drugs into the lateral ventricles of the cat. J. Physiol. (Lond.) 123, 148–167.Google Scholar
  27. Ferkany, J. W., Valentine, H., Stone, G., and Williams, M. (1986) Adenosine A-1 receptors in mammalian brain: Species differences in their interactions with agonists and antagonists. Drug Dey. Res. 9, 85–93.CrossRefGoogle Scholar
  28. Fredholm, B. and Dunwiddie, T. V. (1988) How does adenosine inhibit neurotransmitter release? Trends Pharmacol. Sci. 9, 130–134.PubMedCrossRefGoogle Scholar
  29. Fredholm, B. B. and Hedqvist, P. (1980) Modulation of neurotransmission by pur- ine nucleotides and nucleosides. Biochem. Pharmacol. 29, 1633–1643.CrossRefGoogle Scholar
  30. Fredholm, B. B., Jonzon, B., Lindgren, E., and Lindstrom, K. (1982) Adenosine receptors mediating cyclic AMP production in the rat hippocampus. J. Neurochem. 39, 165–175.PubMedCrossRefGoogle Scholar
  31. Geiger, J. D. and Nagy, J. I. (1989) Adenosine deaminase and [3H]nitrobenzylthioinosine as markers of adenosine metabolism and transport in central purinergic systems, in The Adenosine Receptors (Williams, M., ed.), Humana, Clifton, New Jersey, in press.Google Scholar
  32. Gilfillan, A. M., Wiggan, G. A., and Welton, A. F. (1989) The release of leukotriene C4 (LTC4) and histamine (H) from RBL 2H3 cells in response to adenosine (A) analogs. FASEB J. 3, A907.Google Scholar
  33. Goodman, R. R. and Snyder, S. H. (1982) Autoradiographic localization of adenosine receptors in rat brain using rHicyclohexyladenosine. J. Neurosci. 2, 1230–1241.PubMedGoogle Scholar
  34. Green, H. N. and Stoner, H. B. (1950) Biological Actions of Adenine Nucleotides, ( Lewis, London).Google Scholar
  35. Hamprecht, B. and Van Calker, D. (1985) Nomenclature of adenosine receptors. Trends Pharmacol. Sci. 6, 153, 154.CrossRefGoogle Scholar
  36. Harms, H. H., Wardeh, G. and Mulder, A. H. (1978) Adenosine modulates depolarization-induced release of 3H-noradrenaline from slices of rat brain neocortex. Eur. J. Pharmacol. 49, 305–309.PubMedCrossRefGoogle Scholar
  37. Haslam, R. J., Davidson, M. L. and Desjardins, T. (1978) Inhibition of adenylate cyclase by adenosine analogues in preparations of broken and intact human platelets. Evidence for the unidirectional control of platelet function by cyclic AMP. Biochem. J. 176, 83–95.PubMedGoogle Scholar
  38. Honey, R. M., Ritchie, W. T., and Thomson, W. A. R. (1930) The action of adenosine upon the human heart. J. Med. 23, 485–490.Google Scholar
  39. Hutchison, A. J., Webb, R. L., Oei, H. H., Ghai, G. R., Zimmerman, M., and Williams, M. (1989) CGS21680C, an A2 selective adenosine receptor agonist with preferential hypotensive activity. J. Pharmacol. Exp. Ther. 251, 47–55.PubMedGoogle Scholar
  40. Jarvis, M. F. (1988) Autoradiographic localization and characterization of brain adenosine receptor subtypes, in Receptor Localization: Ligand Autoradiography ( Leslie, F. M. and Altar, C. A., eds.), Liss, New York, pp. 95–111.Google Scholar
  41. Jezer, A., Oppenheimer, B. S., and Schwartz, S. P. (1933) The effect of adenosine on cardiac irregularities in man. Am. Heart J. 9, 252–258.CrossRefGoogle Scholar
  42. Jonzon, B. and Fredholm, B. B. (1985) Release of purines, noradrenaline and GABA from rat hippocampal slices by field stimulation. J. Neurochem. 44, 217–224.PubMedCrossRefGoogle Scholar
  43. Kakiuchi, S., Rall, T. W., and McIlwain, H. (1968) The effect of electrical stimulation upon the accumulation of adenosine 3’,5’-phosphate in isolated cerebral tissue. J. Neurochem. 16, 485–491.CrossRefGoogle Scholar
  44. Kuroda, Y. and Mcllwain, H. (1973) Subcellular localization of [14C]adenine derivatives newly formed in cerebral tissues and the effects of electrical stimulation. J. Neurochem. 21, 889–900.PubMedCrossRefGoogle Scholar
  45. Kuroda, Y. and Mcllwain, H. (1974) Uptake and release of [14C]adenine derivatives in beds of mammalian cortical synaptosomes in a superfusion system. J. Neurochem. 22, 691–699.PubMedCrossRefGoogle Scholar
  46. Lohse, M. J., Klotz, K.-N., Schwabe, U., Cristalli, G., Vittori, S., and Grifantini, M. (1988) 2-Chloro-N6-cyclopentyl adenosine: A highly selective agonist at A1 adenosine receptors. Naunyn-Schmiedebergs Arch. Pharmacol. 337, 687–689.PubMedGoogle Scholar
  47. Londos, C. and Wolff, J. (1977) Two distinct adenosine-sensitive sites on adenylate cyclase. Proc. Natl. Acad. Sci. USA 74, 5482–5486.PubMedCrossRefGoogle Scholar
  48. Miyashita, Y., Kumazawa, T., and Fuiji, R. (1984) Receptor mechanisms in fish chromatophores—IV. Adenosine receptors mediate pigment dispersion in guppy and catfish melanophores. Comp. Biochem. Physiol. 77C, 471–476.Google Scholar
  49. Miyashita, Y., Kumazawa, T., and Fuiji, R. (1984) Receptor mechanisms in fish chromatophores—IV. Adenosine receptors mediate pigment dispersion in guppy and catfish melanophores. Comp. Biochem. Physiol. 77C, 471–476.Google Scholar
  50. Nagy, J. I., La Bella, F., Buss, M., and Dadonna, P. E. (1984) Immunohistochemistry of adenosine deaminase: Implications for adenosine neurotransmission. Science 224, 166–168.PubMedCrossRefGoogle Scholar
  51. Newby, A. C. (1984) Adenosine and the concept of “retaliatory metabolites.” Trends Biochem. 9, 42–44.CrossRefGoogle Scholar
  52. Novales, R. R. and Fuiji, R. (1970) A melanin-dispersing effect of cyclic adenosine monophosphate on Fundulus melanophores. J. Cell. Physiol. 75, 133–136.PubMedCrossRefGoogle Scholar
  53. Oshima, N., Furuuchi, T., and Fujii, R. (1986) Cyclic nucleotide action is mediated through adenosine receptors in damselfish motile iridophores. Comp. Biochem. Physiol. 85C, 89–93.Google Scholar
  54. Pool, R. (1989) Is it healthy to be chaotic? Science 243, 604–607.PubMedCrossRefGoogle Scholar
  55. Phillis, J W. (1989) Adenosine in the control of the cerebral circulation. Cerebrovasc. Brain Metab. Rev. 1, 26–54.PubMedGoogle Scholar
  56. Pull, I. and McIlwain, H. (1972) Adenine derivatives as neurohumoral agents in the brain. The quantities liberated on excitation of superfused cerebral tissues. Biochem. J. 130, 975–981.PubMedGoogle Scholar
  57. Riberio, J. A. and Sebastiao, A. M. (1986) Adenosine receptors and calcium: Basis for proposing a third (A3) adenosine receptor. Prog. Neurobiol. 26, 179–209.CrossRefGoogle Scholar
  58. Roth, J., LeRoith, D., Collier, E. S., Watkinson, A., and Lesniak, M. A. (1986) The evolutionary origins of intercellular communication and the Maginot Lines of the mind. Ann. NY Acad. Sci. 463, 1–11.PubMedCrossRefGoogle Scholar
  59. Sauin, A. and Rall, T. W. (1970) The effect of adenosine and adenine nucleotides on the cyclic adenosine 3’-5-phosphate content of guinea pig cerebral cortex slices. Mol. Pharmacol. 6, 13 23.Google Scholar
  60. Schmitt, F. O. (1982) A protocol for molecular neuroscience, in Molecular Genetic Neuroscience (Schmitt, F. O., Bird, S. J., and Bloom, F. E., eds.) Raven, New York, pp. 1–9.Google Scholar
  61. Schwabe, U. (1988) Use of radioligands in the study of adenosine receptors, in Adenosine and Adenine Nucleotides. Physiology and Pharmacology. ( Paton, D. M., ed.) Taylor and Francis, London, pp. 3–16.Google Scholar
  62. Seale, T. W., Abla, K. A., Shamim, M. T., Carney, J. M., and Daly, J. W. (1988) 3,7Dimethyl-1-propargylxanthine: A potent and selective in vivo agonist of adenosine analogs. Life Sci. 43, 1671–1684.PubMedCrossRefGoogle Scholar
  63. Stokker, G.E., Alberts, A. W., Gilfillan, J. L., Huff, J. W., and Smith, R. L. (1986) 3-Hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors. 5,6-(fluren9-yl) and 6-(fluoren-9-ylideny1)-3,5-dihydroxyhexanoic caids and their lac-tone derivatives. J. Med. Chem. 29, 852–855.PubMedCrossRefGoogle Scholar
  64. Stone, G. A., Jarvis, M. F., Sills, M. A., Weeks, B., Snowhill, E. A., and Williams, M. (1988) Species differences in high affinity adenosine A2 binding sites in strital membranes from mammalian brain. Drug Dev. Res. 15, 31–46.CrossRefGoogle Scholar
  65. Stone, T. W. (1981) Physiological roles for adenosine and adenosine 5’-triphosphate in the nervous system. Neurosci. 6, 523–545.CrossRefGoogle Scholar
  66. Stone, T. W. (1985) Summary of a discussion on purine receptor nomenclature. In Purines: Pharmacology and Physiological Roles ( Stone, T. W., ed.), VCH, Deerfield Beach, Florida, pp. 1–4.Google Scholar
  67. Stone, T. W. (1985) Summary of a discussion on purine receptor nomenclature. In Purines: Pharmacology and Physiological Roles ( Stone, T. W., ed.), VCH, Deerfield Beach, Florida, pp. 1–4.Google Scholar
  68. Trivedi, B. K., Bridges, A. J., Patt, W. C., Priebe, S. R., and Bruns, R. F. (1989) N6bicycloalkyl adenosines with unusually high potency and selectivity for the adenosine A’ receptor. J. Med. Chem. 32, 8–11.PubMedCrossRefGoogle Scholar
  69. Trivedi, B. K., Bridges, A. J., Patt, W. C., Priebe, S. R., and Bruns, R. F. (1989) N6bicycloalkyl adenosines with unusually high potency and selectivity for the adenosine A’ receptor. J. Med. Chem. 32, 8–11.PubMedCrossRefGoogle Scholar
  70. Ukena, D., Shamim, M., Padgett, W., and Daly, J. W. (1986) Analogs of caffeine with selectivity for A2 adenosine receptors. Life Sci. 39, 743–750.PubMedCrossRefGoogle Scholar
  71. Van Calker, D., Muller, M., and Hamprecht, B. (1979) Adenosine regulates via two different types of receptors the accumulation of cyclic AMP in cultured brain cells. J. Neurochem. 33, 999–1005.PubMedCrossRefGoogle Scholar
  72. Varney, C. J. and Skidmore, I. F. (1985) Characterization of the adenosine receptor responsible for the enhancement of mediator release from rat mast cells, in Purines: Pharmacology and Physiological Roles (Stone, T.W., ed.), VCH, Deerfield Beach, Florida, p. 275.Google Scholar
  73. Williams, M. (1987) Purine receptors in mammalian tissues: Pharmacology and functional significance. Annu. Rev. Pharmacol. Toxicol. 27, 315–345.PubMedCrossRefGoogle Scholar
  74. Williams, M. (1989) Adenosine: The prototypic neuromodulator. Neurochem. Inter. 14, 249–264.CrossRefGoogle Scholar
  75. Williams, M. and Jacobson, K. A. (1990) Radioligand binding assays for adenosine receptors, in Adenosine and Adenosine Receptors ( Williams, M., ed.), Humana, Clifton, New Jersey, this volume.Google Scholar
  76. Williams, M. and Olsen, R. A. (1988) Benzodiazepine receptors and tissue function, in Receptor Pharmacology and Function ( Williams, M., Glennon, R. A., and Timmermans, P. B.M.W. M., eds.), Dekker, New York, pp. 385–413.Google Scholar
  77. Williams, M. and Risley, E. A. (1980) Binding of 3H-adenyl-5-imidodiphosphate (AppNHp) to rat brain synaptic membranes. Fed. Proc. 39, 1009 Abstr.Google Scholar
  78. Williams, M.,Wasley, J. F., and Petrack, B. A. (1987b) Antianxiety agents: The benzodiazepine receptor and beyond. Chimica Oggi, September 1987, 11–16.Google Scholar
  79. Williams, M., Francis, J., Ghai, G., Braunwalder, A., Psychoyos, S., Stone, G. A., and Cash, W. D. (1987a) Biochemical characterization of the triazoloquinazoline, CGS 15943A, a novel, non-xanthine adenosine antagonist. J. Pharmacol. Exp. Ther. 241, 415–420.PubMedGoogle Scholar
  80. Winbury, M. M., Papierski, D. H., Hemmer, M. L., and Hambourger, W. E. (1953) Coronary dilator action of the adenine-ATP series. J. Pharmacol. Exp. Ther. 109, 255–260.PubMedGoogle Scholar
  81. Winn, H. R., Morii, S., and Berne, R. M. (1985) The role of adenosine in autoregulation of cerebral blood flow. Ann. Biomed. Eng. 13, 321–328.PubMedCrossRefGoogle Scholar
  82. Wolf, M. M. and Berne, R. M. (1965) Coronary vasodilator properties of purine and pyrimidine derivatives. Circ. Res. 4, 343–348.Google Scholar

Copyright information

© The Humana Press Inc. 1990

Authors and Affiliations

  • Michael Williams

There are no affiliations available

Personalised recommendations