Xanthines as Adenosine Receptor Antagonists

  • Christa E. MüllerEmail author
  • Kenneth A. Jacobson
Part of the Handbook of Experimental Pharmacology book series (HEP, volume 200)


The natural plant alkaloids caffeine and theophylline were the first adenosine receptor (AR) antagonists described in the literature. They exhibit micromolar affinities and are non-selective. A large number of derivatives and analogues were subsequently synthesized and evaluated as AR antagonists. Very potent antagonists have thus been developed with selectivity for each of the four AR subtypes.


Adenosine receptors A1 receptor antagonists A2A receptor antagonists A2B receptor antagonists A3 receptor antagonists Caffeine Deazaxanthines Molecular probes Paraxanthine Theobromine Theophylline Tricyclic xanthine derivatives Xanthines 



CEM is grateful for support by BMBF (BioPharma - Neuroallianz), DFG, DAAD, European Commission (ERANET Neuron), and the State of North-Rhine Westfalia (NRW International Research Graduate Schools BIOTECH-PHARMA and Chemical Biology). KAJ acknowledges support from the Intramural Research Program of NIIDK, NIH.


  1. Abo-Salem OM, Hayallah AM, Bilkei-Gorzo A, Filipek B, Zimmer A, Müller CE (2004) Antinociceptive effects of novel A2B adenosine receptor antagonists. J Pharmacol Exp Ther 308:358–366PubMedCrossRefGoogle Scholar
  2. Alexander SP, Cooper J, Shine J, Hill SJ (1996) Characterization of the human brain putative A2B adenosine receptor expressed in Chinese hamster ovary (CHO.A2B4) cells. Br J Pharmacol 119:1286–1290PubMedCrossRefGoogle Scholar
  3. Antoniou K, Daifoti-Papadopoulou Z, Hyphantis T, Papathanasiou G, Bekris E, Marselos M, Panlilio L, Müller CE, Goldberg SR, Ferré S (2005) A detailed behavioural analysis of the acute motor effects of caffeine in the rat: involvement of adenosine A1 and A2A receptors. Psychopharmacology 183:154–162PubMedCrossRefGoogle Scholar
  4. Akkari R, Burbiel JC, Hockemeyer J, Müller CE (2006) Recent progress in the development of adenosine receptor ligands as antiinflammatory drugs. Curr Top Med Chem 6:1375–1399PubMedCrossRefGoogle Scholar
  5. Auchampach JA, Jin X, Wan TC, Caughey GH, Linden J (1997) Canine mast cell adenosine receptors: cloning and expression of the A3 receptor and evidence that degranulation is mediated by the A2B receptor. Mol Pharmacol 52:846–860PubMedGoogle Scholar
  6. Auchampach JA, Kreckler LM, Wan TC, Maas JE, van der Hoeven D, Gizewski E, Narayanan J, Maas GE (2009) Characterization of the A2B adenosine receptor from mouse, rabbit, and dog. J Pharm Exp Ther 329:2–13CrossRefGoogle Scholar
  7. Balo MC, Brea J, Caamano O, Fernandez F, Garcia-Mera X, Lopez C, Loza MI, Nieto MI, Rodriguez-Borges JE (2009) Synthesis and pharmacological evaluation of novel 1- and 8-substituted 3-furfurylxanthines as adenosine receptor antagonists. Bioorg Med Chem 17:6755–6760PubMedCrossRefGoogle Scholar
  8. Baraldi PG, Tabrizi MA, Preti D, Bovero A, Romagnoli R, Fruttarolo F, Zaid NA, Moorman AR, Varani K, Gessi S, Merighi S, Borea PA (2004) Design, synthesis, and biological evaluation of new 8-heterocyclic xanthine derivatives as highly potent and selective human A2B adenosine receptor antagonists. J Med Chem 47:1434–1447PubMedCrossRefGoogle Scholar
  9. Baraldi PG, Preti D, Tabrizi MA, Fruttarolo F, Romagnoli R, Zaid NA, Moorman AR, Merighi S, Varani K, Borea PA (2005) New pyrrolo[2,1-f]purine-2, 4-dione and imidazo[2,1-f]purine-2, 4-dione derivatives as potent and selective human A3 adenosine receptor antagonists. J Med Chem 48:4697–4701PubMedCrossRefGoogle Scholar
  10. Baraldi PG, Tabrizi MA, Gessi S, Borea PA (2008) Adenosine receptor antagonists: translating medicinal chemistry and pharmacology into clinical utility. Chem Rev 108:238–263PubMedCrossRefGoogle Scholar
  11. Barone S, Churchill PC, Jacobson KA (1989) Adenosine receptor prodrugs: towards kidney-selective dialkylxanthines. J Pharm Exp Ther 250:79–85Google Scholar
  12. Bauer A, Ishiwata K (2009) Adenosine receptor ligands and PET imaging of the CNS. Handb Exp Pharmacol 193:617–642PubMedCrossRefGoogle Scholar
  13. Baumgold J, Nikodijevic O, Jacobson KA (1992) Penetration of adenosine antagonists into mouse brain as determined by ex vivo binding. Biochem Pharmacol 43:889–894PubMedCrossRefGoogle Scholar
  14. Bertarelli DCG, Diekmann M, Hayallah AM, Rüsing D, Iqbal J, Preiss B, Verspohl EJ, Müller CE (2006) Characterization of human and rodent native and recombinant adenosine A2B receptors by radioligand binding studies. Purinergic Signal 2:559–571PubMedCrossRefGoogle Scholar
  15. Bilkei-Gorzo A, Abo-Salem OM, Hayallah AM, Michel K, Müller CE, Zimmer A (2008) Adenosine receptor subtype-selective antagonists in inflammation and hyperalgesia. Naunyn Schmiedebergs Arch Pharmacol 377:65–76PubMedCrossRefGoogle Scholar
  16. Blum D, Galas M-C, Pintor A, Brouillet E, Ledent C, Müller CE, Bantubungi K, Galluzzo M, Gall D, Cuvelier L, Rolland A-S, Popoli P, Schiffmann SN (2003) A dual role of adenosine A2A receptors in the modulation of 3-nitropropionic acid-induced striatal lesions: implications for the neuroprotective potential of A2A antagonists. J Neurosci 23:5361–5369PubMedGoogle Scholar
  17. Boring DL, Ji XD, Zimmet J, Taylor KE, Stiles GL, Jacobson KA (1991) Trifunctional agents as a design strategy for tailoring ligand properties: Irreversible inhibitors of A1 adenosine receptors. Bioconjug Chem 2:77–88PubMedCrossRefGoogle Scholar
  18. Borrmann T, Hinz S, Bertarelli DCG, Li W, Florin NC, Scheiff AB, Müller CE (2009) 1-Alkyl-8-(piperazine-1-sulfonyl)phenylxanthines: development and characterization of adenosine A2B receptor antagonists and a new radioligand with subnanomolar affinity and subtype specificity. J Med Chem 52:3994–4006PubMedCrossRefGoogle Scholar
  19. Brackett LE, Daly JW (1994) Functional characterization of the A2b adenosine receptor in NIH 3T3 fibroblasts. Biochem Pharmacol 47:801–814PubMedCrossRefGoogle Scholar
  20. Briddon SJ, Middleton RJ, Cordeaux Y, Flavin FM, Weinstein JA, George MW, Kellam B, Hill SJ (2004) Quantitative analysis of the formation and diffucion of A1-adenosine receptor-antagonist complexes in single living cells. Proc Natl Acad Sci USA 101:4673–4678PubMedCrossRefGoogle Scholar
  21. Bridson PK, Lin X, Mleman N, Ji XD, Jacobson KA (1998) Synthesis and adenosine receptor affinity of 7-β-D-ribofuranosylxanthine. Nucleosides Nucleotides 17:759–768PubMedCrossRefGoogle Scholar
  22. Brooks DJ, Doder M, Osman S, Luthra SK, Hirani E, Hume S, Kase H, Kilborn J, Martindill S, Mori A (2008) Positron emission tomography analysis of [11C]KW-6002 binding to human and rat adenosine A2A receptors in the brain. Synapse 62:671–681PubMedCrossRefGoogle Scholar
  23. Bruns RF (1981) Adenosine antagonism by purines, pteridines and benzopteridines in human fibroblasts. Biochem Pharmacol 30:325–333PubMedCrossRefGoogle Scholar
  24. Bruns RF, Daly JW, Snyder SH (1980) Adenosine receptors in brain membranes: binding of N6-cyclohexyl[3H]adenosine and 1,3-diethyl-8-[3H]phenylxanthine. Proc Natl Acad Sci USA 77:5547–5551PubMedCrossRefGoogle Scholar
  25. Bruns RF, Lu GH, Pugsley TA (1986) Characterization of the A2 adenosine receptor labeled by [3H]NECA in rat striatal membranes. Mol Pharmacol 29:331–346PubMedGoogle Scholar
  26. Bruns RF, Lu GH, Pugsley TA (1987a) In: Gerlach E, Becker BF (eds) Topics and perspectives in adenosine research. Springer, New York, pp 59–73Google Scholar
  27. Bruns RF, Fergus JH, Badger EW, Bristol JA, Santay LA, Hays SJ (1987b) PD 115, 199: an antagonist ligand for adenosine A2 receptors. Naunyn Schmiedebergs Arch Pharmacol 335:64–69PubMedCrossRefGoogle Scholar
  28. Bruns RF, Fergus JH (1989) Solubilities of adenosine antagonists determined by radioreceptor assay. J Pharm Pharmacol 41:590–594PubMedCrossRefGoogle Scholar
  29. Bulicz J, Bertarelli DCG, Baumert D, Fülle F, Müller CE, Heber D (2006) Synthesis and pharmacology of pyrido[2,3-d]pyrimidinediones bearing polar substituents as adenosine receptor antagonists. Bioorg Med Chem 14:2837–2849PubMedCrossRefGoogle Scholar
  30. Burbiel J, Thorand M, Müller CE (2003) Improved efficient synthesis for multigram-scale production of PSB-10, a potent antagonist at human A3 adenosine receptors. Heterocycles 60:1425–1432CrossRefGoogle Scholar
  31. Cacciari B, Pastorin G, Spalluto G (2003) Medicinal chemistry of A2A adenosine receptor antagonists. Curr Top Med Chem 3:403–411PubMedCrossRefGoogle Scholar
  32. Cagnina RE, Ramos SI, Marshall MA, Wang G, Frazier CR, Linden J (2009) Adenosine A2B receptors are highly expressed on murine type II alveolar epithelial cells. Am J Physiol Lung Cell Mol Physiol 297:L467–L474PubMedCrossRefGoogle Scholar
  33. Carotti A, Cadavid MI, Centeno NB, Esteve C, Loza MI, Martinez A, NietoR RE, Sanz F, Segarra V, Sotelo E, Stefanachi A, Vidal B (2006) Design, synthesis, and structure-activity relationships of 1-, 3-, 8- and 9-substituted 9-deazaxanthines at the human A2B adenosine receptor. J Med Chem 49:282–299PubMedCrossRefGoogle Scholar
  34. Carriba P, Ortiz O, Patkar K, Justinova Z, Stroik J, Themann A, Müller C, Woods AS, Hope BT, Ciruela F, Casado V, Canela EI, Lluis C, Goldberg SR, Moratalla R, Franco R, Ferré S (2007) Striatal adenosine A2A and cannabinoid CB1 receptors form functional heteromeric complexes that mediate the motor effects of cannabinoids. Neuropsychopharmacology 32:2249–2259PubMedCrossRefGoogle Scholar
  35. Ceccarelli S, Altobelli M, D’Alessandro A, Paesano A (1995) A novel hydrophilic 8-cycloalkylxanthine derivative (IRFI 117) is a highly selective antagonist at A1 adenosine receptors. Res Commun Mol Pathol Pharmacol 87:101–102Google Scholar
  36. Cirillo R, Barone D, Franzone JS (1988) Doxofylline, an antiasthmatic drug lacking affinity for adenosine receptors. Arch Int Pharmacodyn Ther 295:221–237PubMedGoogle Scholar
  37. Cohen BE, Lee G, Jacobson KA, Kim YC, Huang Z, Sorscher E, Pollard HB (1997) CPX (1,3-dipropyl-8-cyclopentylxanthine) and other alkyl-xanthines differentially bind to wild type and DF508 mutant first nucleotide binding fold (NBF-1) domains of the cystic fibrosis transmembrane conductance regulator. Biochemistry 36:6455–6461PubMedCrossRefGoogle Scholar
  38. Cristalli G, Cacciari B, Dal Ben D, Lambertucci C, Moro S, Spalluto G, Volpini R (2007) Highlights on the development of A2A adenosine receptor agonists and antagonists. ChemMedChem 2:260–281PubMedCrossRefGoogle Scholar
  39. Cristalli G, Müller CE, Volpini G (2009) Recent development in adenosine A2A receptor ligands. In: Wilson CN, Mustafa SJ (eds) Handbook of experimental pharmacology 193: adenosine receptors in health and disease, Springer Verlag, Berlin, pp 59–98Google Scholar
  40. Cunha GM, Canas PM, Melo CS, Hockemeyer J, Müller CE, Oliveira CR, Cunha RA (2008) Adenosine A2A receptor blockade prevents memory dysfunction caused by beta-amyloid peptides but not by scopolamine or MK-801. Exp Neurol 210:776–781PubMedCrossRefGoogle Scholar
  41. Dall’Igna OP, Fett P, Gomes MW, Souza DO, Cunha RA, Lara DR (2007) Caffeine and adenosine A2A receptor antagonists prevent beta-amyloid (25-35)-induced cognitive deficits in mice. Exp Neurol 203:241–245PubMedCrossRefGoogle Scholar
  42. Daly JW (1982) Adenosine receptors: targets for future drugs. J Med Chem 25:197–207PubMedCrossRefGoogle Scholar
  43. Daly JW, Padgett W, Shamim MT, Butts-Lamb P, Waters J (1985) 1, 3-Dialkyl-8-(p-sulfophenyl)xanthines: potent water-soluble antagonists for A1- and A2-adenosine receptors. J Med Chem 28:487–492PubMedCrossRefGoogle Scholar
  44. Daly JW, Padgett WL, Shamim MT (1986a) Analogues of caffeine and theophylline: effect of structural alterations on affinity at adenosine receptors. J Med Chem 29:1305–1308PubMedCrossRefGoogle Scholar
  45. Daly JW, Padgett WL, Shamim MT (1986b) Analogues of 1,3-dipropyl-8-phenylxanthine: enhancement of selectivity at A1-adenosine receptors by aryl substituents. J Med Chem 29:1520–1524PubMedCrossRefGoogle Scholar
  46. Daly JW, Hide I, Müller CE, Shamim M (1991) Caffeine analogs: structure-activity relationships at adenosine receptors. Pharmacology 42:309–321PubMedCrossRefGoogle Scholar
  47. Daly JW (1991) Analogs of caffeine and theophylline: activity as antagonists at adenosine receptors. In: Imai S, Nakazawa M (eds) Role of adenosine and adenine nucleotides in the biological system. Amsterdam, Elsevier, pp 119–129Google Scholar
  48. Daly JW, Jacobson KA (1995) Adenosine and adenine nucleotides: from molecular biology to integrative physiology. Kluwer, Boston, 155Google Scholar
  49. Daly JW (2000) Alkylxanthines as research tools. J Auton Nerv Syst 81:44–52PubMedCrossRefGoogle Scholar
  50. Daly JW (2007) Caffeine analogs: biomedical impact. Cell Mol Life Sci 64:2153–2169PubMedCrossRefGoogle Scholar
  51. Del Giudice MR, Borioni A, Mustazza C, Gatta F, Dionisotti S, Zocchi C, Ongini E (1996) (E)-1-(Heterocyclyl or cyclohexyl)-2-[1,3,7-trisubstituted(xanthin-8-yl)]ethenes as adenosine A2A receptors antagonists. Eur J Med Chem 31:59–63CrossRefGoogle Scholar
  52. Doggrell SA (2005) BG-9928 (Biogen Idec). Curr Opin Investig Drugs 6:962–968PubMedGoogle Scholar
  53. Drabczynska A, Schumacher B, Müller CE, Karolak-Wojciechowska J, Michalak B, Pekala E, Kiec-Kononowicz K (2003) Impact of the aryl substituent kind and distance from pyrimido[2,1-f]purindiones on the adenosine receptor selectivity and antagonistic properties. Eur J Med Chem 38:397–402PubMedCrossRefGoogle Scholar
  54. Drabczynska A, Müller CE, Schumacher B, Hinz S, Karolak-Wojciechowska J, Michalak B, Pekala E, Kiec-Kononowicz K (2004) Tricyclic oxazolo[2,3-f]purinediones: potency as adenosine receptor ligands and anticonvulsants. Bioorg Med Chem 12:4895–4908PubMedCrossRefGoogle Scholar
  55. Drabczynska A, Müller CE, Lacher SK, Schumacher B, Karolak-Wojciechowska J, Nasal A, Kawczak P, Yuzlenko O, Pekala E, Kiec-Kononowicz K (2006) Synthesis and biological activity of tricyclic aryloimidazo-, pyrimido-, and diazepinopurinediones. Bioorg Med Chem 14:7258–7281PubMedCrossRefGoogle Scholar
  56. Drabczynska A, Müller CE, Karolak-Wojciechowska J, Schumacher B, Schiedel A, Yuzlenko O, Kiec-Kononowicz K (2007a) N9-Benzyl-substituted 1,3-dimethyl- and 1,3-dipropyl-pyrimido-[2,1-f]purinediones: synthesis and structure-activity relationships at adenosine A1 and A2A receptors. Bioorg Med Chem 15:5003–5017PubMedCrossRefGoogle Scholar
  57. Drabczynska A, Müller CE, Schiedel A, Schumacher B, Karolak-Wojciechowska J, Fruzinski A, Zobnina W, Yuzlenko O, Kiec-Kononowicz K (2007b) Phenylethyl-substituted pyrimido[2,1-f]purinediones and related compounds: structure-activity relationships as adenosine A1 and A2A receptor ligands. Bioorg Med Chem 15:6956–6974PubMedCrossRefGoogle Scholar
  58. Elzein E, Kalla RV, Li X, Perry T, Gimbel A, Zeng D, Lustig D, Leung K, Zablocki J (2008) Discovery of a novel A2B adenosine receptor antagonist as a clinical candidate for chronic inflammatory airway diseases. J Med Chem 51:2267–2278PubMedCrossRefGoogle Scholar
  59. Erickson RH, Hiner RN, Feeney SW, Blake PR, Rzeszotarski WJ, Hicks RP, Costello DG, Abreu ME (1991) 1,3,8-Trisubstituted xanthines. Effects of substitution pattern upon adenosine receptor A1/A2 affinity. J Med Chem 34:1431–1435PubMedCrossRefGoogle Scholar
  60. Esteve C, Nueda JL, Beleta J, Cardenas A, Lozoya E, Cadavid MI, Loza MI, Ryder H, Vidal B (2006) New pyrrolopyrimidin-6-ylbenzyenesulfonamides: potent A2B adenosine receptor antagonists. Bioorg Med Chem Lett 16:3642–3645PubMedCrossRefGoogle Scholar
  61. Farrar AM, Pereira M, Velasco F, Hockemeyer J, Müller CE, Salamone J (2007) Adenosine A2A receptor antagonism reverses the effects of dopamine receptor antagonism on instrumental output and effort-related choice in the rat: implications for studies of psychomotor slowing. Psychopharmacology 191:579–586PubMedCrossRefGoogle Scholar
  62. Ferkany JW, Valentine HL, Stone GA, Williams M (1986) Adenosine A1 receptors in mammalian brain: species differences in their interactions with agonists and antagonists. Drug Dev Res 9:85–93CrossRefGoogle Scholar
  63. Fernandez HH, Greeley DR, Zweig RM, Wojcieszek J, Mori A, Sussman NM, 6002-US-051 Study Group (2010) Istradefylline as monotherapy for Parkinson disease: results of the 6002-US-051 trial. Parkinsonism Relat Disord 16:16–20PubMedCrossRefGoogle Scholar
  64. Ferré S, Popoli P, Giménez-Llort L, Rimondini R, Müller CE, Strömberg I, Ögren SO, Fuxe K (2001) Adenosine/dopamine interaction: implication for the treatment of Parkinson’s disease. Parkinsonism Relat Disord 7:235–241PubMedCrossRefGoogle Scholar
  65. Ferré S, Ciruela F, Borycz J, Solinas M, Quarta D, Antoniou K, Quiroz C, Justinova Z, Lluis C, Franco R, Goldberg SR (2008) Adenosine A1–A2A receptor heteromers: new targets for caffeine in the brain. Front Biosci 13:2391–2399PubMedCrossRefGoogle Scholar
  66. Fhid O, Pawlowski M, Jurczyk S, Müller CE, Schumacher B (2003) Pyridin-8-on[2,1-f]theophylline-9-alkylcarboxylic acid amides as A1 and A2A adenosine receptor ligands. Farmaco 58:439–444PubMedCrossRefGoogle Scholar
  67. Filip M, Frankowska M, Zaniewska M, Przegalinski E, Müller CE, Agnati LF, Franco R, Roberts DCS, Fuxe K (2006) Involvement of adenosine A2A and dopamine receptors in the locomotor and sensitizing effects of cocaine. Brain Res 1077:67–80PubMedCrossRefGoogle Scholar
  68. Fozard JR, Baur F, Wolber C (2003) Antagonist pharmacology of adenosine A2B receptors from rat, guinea pig and dog. Eur J Pharmacol 475:79–84PubMedCrossRefGoogle Scholar
  69. Franchetti P, Messini L, Cappellacci L, Grifantini M, Lucacchini A, Martini C, Senatore G (1994) 8-Azaxanthine derivatives as antagonists of adenosine receptors. J Med Chem 37:2970–2975PubMedCrossRefGoogle Scholar
  70. Frédérick R, Ooms F, Castagnoli N Jr, Petzer JP, Feng JF, Schwarzschild MA, Van der Schyf CJ, Wouters J (2005) (E)-8-(3-Chlorostyryl)-1,3,7-trimethylxanthine, a caffeine derivative acting both as antagonist of adenosine A2A receptors and as inhibitor of MAO-B. Acta Crystallogr C61:o531–o532Google Scholar
  71. Fredholm BB, Abbracchio MP, Burnstock G, Daly JW, Harden KT, Jacobson KA, Leff P, Williams M (1994) Nomenclature and classification of purinoceptors: a report from the IUPHAR subcommittee. Pharmacol Rev 46:143–156PubMedGoogle Scholar
  72. Fredholm BB, Bättig K, Holmén J, Nehlig A, Zvartau EE (1999) Actions of caffeine in the brain with special reference to factors that contribute to its widespread use. Pharmacol Rev 51:83–133PubMedGoogle Scholar
  73. Fredholm BB, Jacobson KA (2009) John W. Daly and the early characterization of adenosine receptors. Heterocycles 79:73–83CrossRefGoogle Scholar
  74. Fuxe K, Marcellino D, Genedani S, Agnati L (2007) Adenosine A2A receptors, dopamine D2 receptors and their interactions in Parkinson’s disease. Mov Disord 22:1990–2017PubMedCrossRefGoogle Scholar
  75. Gao ZG, Kim SK, Biadatti T, Chen W, Lee K, Barak D, Kim SG, Johnson CR, Jacobson KA (2002) Structural determinants of A3 adenosine receptor activation: nucleoside ligands at the agonist/antagonist boundary. J Med Chem 45:4471–4484PubMedCrossRefGoogle Scholar
  76. Geis U, Grahner B, Pawlowski M, Drabczynska A, Gorczyca M, Müller CE (1995) Tricyclic theophylline derivatives with high water-solubility: structure-activity relationships at adenosine receptors, phosphodiesterases and benzodiazepine binding sites. Pharmazie 50:333–336PubMedGoogle Scholar
  77. Givertz MM (2009) Adenosine A1 receptor antagonists at a fork in the road. Circ Heart Fail 2:519–522PubMedCrossRefGoogle Scholar
  78. Grahner B, Winiwarter S, Lanzner W, Müller CE (1994) Synthesis and structure-activity relationships of deazaxanthines: analogs of potent A1- and A2-adenosine receptor antagonists. J Med Chem 37:1526–1534PubMedCrossRefGoogle Scholar
  79. Hayallah AM, Sandoval-Ramírez J, Reith U, Schobert U, Preiss B, Schumacher B, Daly JW, Müller CE (2002) 1, 8-Disubstituted xanthine derivatives: synthesis of potent A2B-selective adenosine receptor antagonists. J Med Chem 45:1500–1510PubMedCrossRefGoogle Scholar
  80. Hauber W, Nagel J, Sauer R, Müller CE (1998) Motor effects induced by a blockade of adenosine A2A receptors in the caudate-putamen. Neuroreport 9:1803–1806PubMedCrossRefGoogle Scholar
  81. Hauber W, Neuscheler P, Nagel J, Müller CE (2001) Catalepsy induced by a blockade of dopamine D1 or D2 receptors was reversed by a concomitant blockade of A2A receptors in the caudate-putamen of rats. Eur J Neurosci 14:1287–1293PubMedCrossRefGoogle Scholar
  82. Hirani E, Gillies J, Karasawa A, Shimada J, Kase H, Opacka-Juffry J, Osman S, Luthra SK, Hume SP, Brooks DJ (2001) Evaluation of [4-O-methyl-11C]KW-6002 as a potential PET ligand for mapping central adenosine A2A receptors in rats. Synapse 42:164–176PubMedCrossRefGoogle Scholar
  83. Hockemeyer J, Burbiel JC, Müller CE (2004) Multigram-scale syntheses, stability, and photoreactions of A2A adenosine receptor antagonists with 8-styrylxanthine structure: potential drugs for Parkinson’s disease. J Org Chem 69:3308–3318PubMedCrossRefGoogle Scholar
  84. Holschbach MH, Olsson RA, Bier D, Wutz W, Sihver W, Schüller M, Palm B, Coenen HH (2002) Synthesis and evaluation of no-carrier-added 8-cyclopentyl-3-(3-[18F]fluoropropyl)-1-propylxanthine ([18F]CPFPX): a potent and selective A1-adenosine receptor antagonist for in vivo imaging. J Med Chem 45:5150–5156PubMedCrossRefGoogle Scholar
  85. Ilas J, Pekar S, Hockemeyer J, Euler H, Kirfel A, Müller CE (2005) Development of spin-labeled probes for adenosine receptors. J Med Chem 48:2108–2114PubMedCrossRefGoogle Scholar
  86. Ishiwari K, Madson LJ, Farrar AM, Mingote SM, Valenta JP, DiGianvittorio MD, Frank LE, Correa M, Hockemeyer J, Müller CE, Salamone JD (2007) Injections of the selective adenosine A2A antagonist MSX-3 into the nucleus accumbens core attenuate the locomotor suppression induced by haloperidol in rats. Behav Brain Res 178:190–199PubMedCrossRefGoogle Scholar
  87. Ishiwata K, Noguchi J, Toyama H, Sakiyama Y, Koike N, Ishii S, Oda K, Endo K, Suzuki F, Senda M (1996) Synthesis and preliminary evaluation of [11C]KF17837, a selective adenosine A2A antagonist. Appl Radiat Isot 47:507–511PubMedCrossRefGoogle Scholar
  88. Ishiwata K, Sakiyama Y, Sakiyama T, Shimada J, Toyama H, Oda K, Suzuki F, Senda M (1997) Myocardial adenosine A2A receptor imaging of rabbit by PET with [11C]KF17837. Ann Nucl Med 11:219–225PubMedCrossRefGoogle Scholar
  89. Ishiwata K, Noguchi J, Wakabayashi S, Shimada J, Ogi N, Nariai T, Tanaka A, Endo K, Suzuki F, Senda M (2000a) 11C-labeled KF18446: a potential central nervous system adenosine A2A receptor ligand. J Nucl Med 41:345–354PubMedGoogle Scholar
  90. Ishiwata K, Ogi N, Shimada J, Nonaka H, Tanaka A, Suzuki F, Senda M (2000b) Further characterization of a CNS adenosine A2A receptor ligand [11C]KF18446 with in vitro autoradiography and in vivo tissue uptake. Ann Nucl Med 14:81–89PubMedCrossRefGoogle Scholar
  91. Ishiwata K, Shimada J, Wang WF, Harakawa H, Ishii S, Kiyosawa M, Suzuki F, Senda M (2000c) Evaluation of iodinated and brominated [11C]styrylxanthine derivatives as in vivo radioligands mapping adenosine A2A receptor in the central nervous system. Ann Nucl Med 14:247–253PubMedCrossRefGoogle Scholar
  92. Ishiwata K, Ogi N, Hayakawa N, Oda K, Nagaoka T, Toyama H, Suzuki F, Endo K, Tanaka A, Senda M (2002) Adenosine A2A receptor imaging with [11C]KF18446 PET in the rat brain after quinolinic acid lesion: comparison with the dopamine receptor imaging. Ann Nucl Med 16:467–475PubMedCrossRefGoogle Scholar
  93. Ishiwata K, Kawamura K, Kimura Y, Oda K, Ishii K (2003a) Potential of an adenosine A2A receptor antagonist [11C]TMSX for myocardial imaging by positron emission tomography: a first human study. Ann Nucl Med 17:457–462PubMedCrossRefGoogle Scholar
  94. Ishiwata K, Wang WF, Kimura Y, Kawamura K, Ishii K (2003b) Preclinical studies on [11C]TMSX for mapping adenosine A2A receptors by positron emission tomography. Ann Nucl Med 17:205–211PubMedCrossRefGoogle Scholar
  95. Ishiyama H, Nakajima H, Nakata H, Kobayashi J (2009) Synthesis of hybrid analogues of caffeine and eudistomin D and their affinity for adenosine receptors. Bioorg Med Chem 17:4280–4284PubMedCrossRefGoogle Scholar
  96. Jacobson KA, Kirk KL, Padgett W, Daly JW (1985a) Probing the adenosine receptor with adenosine and xanthine biotin conjugates. FEBS Lett 184:30–35PubMedCrossRefGoogle Scholar
  97. Jacobson KA, Kirk KL, Padgett WL, Daly JW (1985b) Functionalized congeners of 1,3-dialkylxanthines: preparation of analogues with high affinity for adenosine receptors. J Med Chem 28:1334–1340PubMedCrossRefGoogle Scholar
  98. Jacobson KA, Ukena D, Kirk KL, Daly JW (1986a) [3H]Xanthine amine congener of 1,3-dipropyl-8-phenylxanthine: an antagonist radioligand for adenosine receptors. Proc Natl Acad Sci USA 83:4089–4093PubMedCrossRefGoogle Scholar
  99. Jacobson KA, Kirk KL, Padgett WL, Daly JW (1986b) A functionalized congener approach to adenosine receptor antagonists: amino acid conjugates of 1,3-dipropylxanthine. Mol Pharmacol 29:126–133PubMedGoogle Scholar
  100. Jacobson KA, Ukena D, Padgett W, Daly JW, Kirk KL (1987a) Xanthine functionalized congeners as potent ligands at A2-adenosine receptors. J Med Chem 30:211–214PubMedCrossRefGoogle Scholar
  101. Jacobson KA, Ukena D, Padgett W, Kirk KL, Daly JW (1987b) Molecular probes for extracellular adenosine receptors. Biochem Pharmacol 36:1697–1707PubMedCrossRefGoogle Scholar
  102. Jacobson KA, Lipowski AW, Moody TW, Padgett W, Pijl E, Kirk KL, Daly JW (1987c) Binary drugs: conjugates of purines and a peptide that bind to both adenosine and substance P receptors. J Med Chem 30:1529–1532PubMedCrossRefGoogle Scholar
  103. Jacobson KA, de la Cruz R, Schulick R, Kiriasis L, Padgett W, Pfleiderer W, Kirk KL, Neumeyer JL, Daly JW (1988) 8-Substituted xanthines as antagonists as A1 and A2-adenosine receptors. Biochem Pharmacol 37:3653–3661PubMedCrossRefGoogle Scholar
  104. Jacobson KA, Barone S, Kammula U, Stiles GL (1989a) Electrophilic derivatives of purines as irreversible inhibitors of A1-adenosine receptors. J Med Chem 32:1043–1051PubMedCrossRefGoogle Scholar
  105. Jacobson KA, Kiriasis L, Barone S, Bradbury BJ, Kammula U, Campagne JM, Daly JW, Neumeyer JL, Pfleiderer W (1989b) Sulfur-containing xanthine derivatives as selective antagonists at A1-adenosine receptors. J Med Chem 32:1873–1879PubMedCrossRefGoogle Scholar
  106. Jacobson KA (1990) Probing adenosine receptors using biotinylated purine conjugates. Methods Enzymol 184:668–671Google Scholar
  107. Jacobson KA, van Galen PJM, Williams M (1992a) Perspective, adenosine receptors: pharmacology, structure activity relationships and therapeutic potential. J Med Chem 35:407–422PubMedCrossRefGoogle Scholar
  108. Jacobson KA, Olah ME, Stiles GL (1992b) Trifunctional ligands: a radioiodinated high affinity acylating antagonist for the A1 adenosine receptor. Pharmacol Commun 1:145–154Google Scholar
  109. Jacobson KA, Gallo-Rodriguez C, Melman N, Fischer B, Maillard M, van Bergen A, van Galen PJ, Karton Y (1993a) Structure-activity relationships of 8-styrylxanthines as A2-selective adenosine antagonists. J Med Chem 36:1333–1342PubMedCrossRefGoogle Scholar
  110. Jacobson KA, Shi D, Gallo-Rodriguez C, Manning M Jr, Müller C, Daly JW, Neumeyer JL, Kiriasis L, Pfleiderer W (1993b) Effect of trifluoromethyl and other substituents on activity of xanthines at adenosine receptors. J Med Chem 36:2639–2644PubMedCrossRefGoogle Scholar
  111. Jacobson KA, Fischer B, Ji XD (1995) A “cleavable trifunctional” approach to receptor affinity labeling: regeneration of binding to A1-adenosine receptors. Bioconjug Chem 6:255–263PubMedCrossRefGoogle Scholar
  112. Jacobson KA (1998) A3 adenosine receptors: novel ligands and paradoxical effects. Trends Pharmacol Sci 19:184–191PubMedCrossRefGoogle Scholar
  113. Jacobson KA, IJzerman AP, Linden J (1999) 1,3-Dialkylxanthine derivatives having high potency as antagonists at human A2B adenosine receptors. Drug Devel Res 47:45–53CrossRefGoogle Scholar
  114. Jacobson KA, Gao ZG (2006) Adenosine receptors as therapeutic targets. Nat Rev Drug Discov 5:247–264PubMedCrossRefGoogle Scholar
  115. Jacobson KA (2009) Functionalized congener approach to the design of ligands for G protein-coupled receptors (GPCRs). Bioconjug Chem 20:1816–1835PubMedCrossRefGoogle Scholar
  116. Jarvis MF, Jacobson KA, Williams M (1987) Autoradiographic localization of adenosine A1 receptors in rat brain using [3H]XCC, a functionalized congener of 1,3-dipropylxanthine. Neurosci Lett 81:69–74PubMedCrossRefGoogle Scholar
  117. Ji XD, Stiles GL, Jacobson KA (1991) [3H]XAC (xanthine amine congener) is a radioligand for A2-adenosine receptors in rabbit striatum. Neurochem Int 18:207–213PubMedCrossRefGoogle Scholar
  118. Ji XD, Gallo-Rodriguez C, Jacobson KA (1993) 8-(3-Isothiocyanatostyryl)caffeine is a selective irreversible inhibitor or striatal A2-adenosine receptors. Drug Dev Res 29:292–298PubMedCrossRefGoogle Scholar
  119. Ji XD, von Lubitz D, Olah ME, Stiles GL, Jacobson KA (1994) Species differences in ligand affinity at central A3-adenosine receptors. Drug Dev Res 33:51–59CrossRefGoogle Scholar
  120. Ji XD, Kim YC, Ahern DG, Linden J, Jacobson KA (2001) [3H]MRS 1754, a selective antagonist radioligand for A2B adenosine receptors. Biochem Pharmacol 61:657–663PubMedCrossRefGoogle Scholar
  121. Kalla R, Elzein E, Perry T, Li X, Gimbel A, Yang M, Zeng D, Zablocki J (2008) Selective, high affinity A2B adenosine receptor antagonists: N-1 monosubstituted 8-(pyrazol-4-yl)xanthines. Bioorg Med Chem Lett 18:1397–1401PubMedCrossRefGoogle Scholar
  122. Kalla R, Zablocki J (2009) Progress in the discovery of selective, high affinity A2B adenosine receptor antagonists as clinical candidates. Purinergic Signal 5:21–29PubMedCrossRefGoogle Scholar
  123. Karcz-Kubicha M, Quarta D, Hope BT, Antoniou K, Müller CE, Morales M, Schindler CW, Goldberg SR, Ferré S (2003a) Enabling role of adenosine A1 receptors in adenosine A2A receptor-mediated striatal expression of c-fos. Eur J Neurosci 18:296–302PubMedCrossRefGoogle Scholar
  124. Karcz-Kubicha M, Antoniou K, Terasmaa A, Quarta D, Solinas M, Justinova Z, Pezzola A, Reggio R, Müller CE, Fuxe K, Goldberg SR, Popoli P, Ferré S (2003b) Involvement of adenosine A1 and A2A receptors in the motor effects of caffeine after its acute and chronic administration. Neuropsychopharmacology 28:1281–1291PubMedCrossRefGoogle Scholar
  125. Kase H (2003) The adenosine A2A receptor selective antagonist KW6002: research toward a novel nondopaminergic therapy for Parkinson’s disease. Neurology 61(Suppl 6):S97–S100PubMedCrossRefGoogle Scholar
  126. Kiec-Kononowicz K, Drabczynska A, Pekala E, Michalak B, Müller CE, Schumacher B, Karolak-Wojciechowska J, Duddeck H, Rockitt S, Wartchow R (2001) New developments in A1 and A2 adenosine receptor antagonists. Pure Appl Chem 73:1411–1420CrossRefGoogle Scholar
  127. Kiesman WF, Zhao J, Conlon PR, Petter RC, Jin X, Smits G, Lutterodt F, Sullivan GW, Linden J (2006a) Norbornyllactone-substituted xanthines as adenosine A1 receptor antagonists. Bioorg Med Chem 14:3654–3661PubMedCrossRefGoogle Scholar
  128. Kiesman WF, Zhao J, Conlon PR, Dowling JE, Petter RC, Lutterodt F, Jin X, Smits G, Fure M, Jayaraj A, Kim J, Sullivan G, Linden J (2006b) Potent and orally bioavailable 8-bicyclo[2.2.2]octylxanthines as adenosine A1 receptor antagonists. J Med Chem 49:7119–7131PubMedCrossRefGoogle Scholar
  129. Kim HO, Ji XD, Melman N, Olah ME, Stiles GL, Jacobson KA (1994a) Structure activity relationships of 1,3-dialkylxanthine derivatives at rat A3-adenosine receptors. J Med Chem 37:3373–3382PubMedCrossRefGoogle Scholar
  130. Kim HO, Ji XD, Melman N, Olah ME, Stiles GL, Jacobson KA (1994b) Selective ligands for rat A3-adenosine receptors: structure-activity relationships of 1,3-dialkylxanthine-7-riboside derivatives. J Med Chem 37:4020–4030PubMedCrossRefGoogle Scholar
  131. Kim YC, Karton Y, Ji XD, Melman N, Linden J, Jacobson KA (1999) Acyl-hydrazide derivatives of a xanthine carboxylic congener (XCC) as selective antagonists at human A2B adenosine receptors. Drug Dev Res 47:178–188CrossRefGoogle Scholar
  132. Kim Y-S, Ji X, Melman N, Linden J, Jacobson KA (2000) Anilide derivatives of an 8-phenylxanthine carboxylic congener are highly potent and selective antagonists at human A2B adenosine receptors. J Med Chem 43:1165–1172PubMedCrossRefGoogle Scholar
  133. Kim S-A, Marschall MA, Melman N, Kim HS, Müller CE, Linden J, Jacobson KA (2002) Structure-activity relationships at human and rat A2B adenosine receptors of xanthine derivatives substituted at the 1-, 3-, 7-, and 8-positions. J Med Chem 45:2131–2138PubMedCrossRefGoogle Scholar
  134. Kirfel A, Schwabenländer F, Müller CE (1997) Crystal structure of 1-propyl-8-(4-sulfophenyl)-7H-imidazo[4,5-d]pyrimidin-2,6(1H,3H)-dione dehydrate, C14H14N4O5S×2 H2O. Z Kristallogr New Cryst Struct 3:447–448Google Scholar
  135. Klotz KN, Vogt H, Tawfik-Schlieper H (1991) Comparison of adenosine receptors in brain from different species by radioligand binding and photoaffinity labelling. Naunyn Schmiedebergs Arch Pharmacol 343:196–201PubMedCrossRefGoogle Scholar
  136. Klotz KN, Hessling J, Hegler J, Owman C, Kull B, Fredholm BB, Lohse MJ (1998) Comparative pharmacology of human adenosine receptor subtypes - characterization of stably transfected receptors in CHO cells. Naunyn Schmiedebergs Arch Pharmacol 357:1–9PubMedCrossRefGoogle Scholar
  137. Knutsen LJ, Weiss SM (2001) KW-6002 (Kyowa Hakko Kogyo). Curr Opin Investig Drugs 2:668–673PubMedGoogle Scholar
  138. Krämer SD, Testa B (2008) The biochemistry of drug metabolism – an introduction part 6. Inter-individual factors affecting drug metabolism. Chem Biodivers 5:2465–2578PubMedCrossRefGoogle Scholar
  139. Kull B, Arslan G, Nilsson C, Owman C, Lorenzen A, Schwabe U, Fredholm BB (1999) Differences in the order of potency for agonists but not antagonists at human and rat adenosine A2A receptors. Biochem Pharmacol 57:65–75PubMedCrossRefGoogle Scholar
  140. Linden J (1994) Cloned adenosine A3 receptors: pharmacological properties, species differences and receptor functions. Trends Pharmacol Sci 15:298–306PubMedCrossRefGoogle Scholar
  141. Linden J, Taylor HE, Robeva AS, Tucker AL, Stehle JH, Rivkees SA, Fink JS, Reppert SM (1993) Molecular cloning and functional expression of a sheep A3 adenosine receptor with widespread tissue distribution. Mol Pharmacol 44:524–532PubMedGoogle Scholar
  142. Linden J, Thai T, Figler H, Jin X, Robeva AS (1999) 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 56:705–713PubMedGoogle Scholar
  143. Marcellino D, Carriba P, Filip M, Borgkvist A, Frankowska M, Bellido I, Tanganelli S, Müller CE, Fisone G, Lluis C, Agnati LF, Franco R, Fuxe K (2008) Antagonistic cannabinoid CB1/dopamine D2 receptor interactions in striatal CB1/D2 heteromers. A combined neurochemical and behavioural analysis. Neuropharmacology 54:815–823PubMedCrossRefGoogle Scholar
  144. Marian T, Boros I, Lengyel Z, Balkay L, Horvath G, Emri M, Sarkadi E, Szentmiklosi AJ, Fekete I, Tron L (1999) Preparation and primary evaluation of [11C]CSC as a possible tracer for mapping adenosine A2A receptors by PET. Appl Radiat Isot 50:887–893PubMedCrossRefGoogle Scholar
  145. Martin PL, Wysocki RJ Jr, Barrett RJ, May JM, Linden J (1996) 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 276:490–499PubMedGoogle Scholar
  146. Massip S, Guillon J, Bertarelli D, Bosc JJ, Leger JM, Lacher S, Bontemps C, Dupont T, Müller CE, Jarry C (2006) Synthesis and preliminary evaluation of new 1- and 3-[1-(2-hydroxy-3-phenoxypropyl)]xanthines from 2-amino-2-oxazolines as potential A1 and A2A adenosine receptor antagonists. Bioorg Med Chem 14:2697–2719PubMedCrossRefGoogle Scholar
  147. Michael S, Warstat C, Michel F, Yan L, Müller CE, Nieber K (2010) Adenosine A2A agonist and A2B antagonist mediate an inhibition of inflammation-induced contractile disturbance of a rat gastrointestinal preparation. Purinergic Signal 6:117–124Google Scholar
  148. Mishina M, Ishiwata K, Kimura Y, Naganawa M, Oda K, Kobayashi S, Katayama Y, Ishii K (2007) Evaluation of distribution of adenosine A2A receptors in normal human brain measured with [11C]TMSX PET. Synapse 61:778–784PubMedCrossRefGoogle Scholar
  149. Moro S, Gao ZG, Jacobson KA, Spalluto G (2006) Progress in the pursuit of therapeutic adenosine receptor antagonists. Med Res Rev 26:131–159PubMedCrossRefGoogle Scholar
  150. Mott AM, Nunes EJ, Collins LE, Port RG, Sink KS, Hockemeyer J, Müller CE, Salamone JD (2009) The adenosine A2A antagonist MSX-3 reverses the effects of the dopamine antagonist haloperidol on effort-related decision making in a T-maze cost/benefit procedure. Psychopharmacology 204:103–112PubMedCrossRefGoogle Scholar
  151. Müller CE (1994) Formation of oxazolo[3,2-a]purinones from propynyluracils. J Org Chem 59:1928–1929CrossRefGoogle Scholar
  152. Müller CE (1997) A1-adenosine receptor antagonists. Expert Opin Ther Patents 7:419–440CrossRefGoogle Scholar
  153. Müller CE (2000) A2A adenosine receptor antagonists - future drugs for Parkinson’s disease? Drugs Future 25:1043–1052CrossRefGoogle Scholar
  154. Müller CE (2001) A3 adenosine receptor antagonists. Mini-Rev Med Chem 1:417–427PubMedCrossRefGoogle Scholar
  155. Müller CE (2003) Medicinal chemistry of adenosine A3 receptor ligands. Curr Top Med Chem 3:445–462PubMedCrossRefGoogle Scholar
  156. Müller CE (2009) Prodrug approaches for enhancing the bioavailability of drugs with low solubility. Chem Biodivers 6:2071–2083PubMedCrossRefGoogle Scholar
  157. Müller CE, Scior T (1993) Adenosine receptors and their modulators. Pharm Acta Helv 68:77–111PubMedCrossRefGoogle Scholar
  158. Müller CE, Shi D, Manning M Jr, Daly JW (1993) Synthesis of paraxanthine analogs (1,7-disubstituted xanthines) and other xanthines unsubstituted at the 3-position: structure-activity relationships at adenosine receptors. J Med Chem 36:3341–3349PubMedCrossRefGoogle Scholar
  159. Müller CE, Stein B (1996) Adenosine receptor antagonists: structures and potential therapeutic applications. Curr Pharm Des 2:501–530Google Scholar
  160. Müller CE, Geis U, Hipp J, Schobert U, Frobenius W, Pawlowski M, Suzuki F, Sandoval-Ramirez J (1997a) Synthesis and structure-activity relationships of DMPX (3,7-dimethyl-1-propargylxanthine) derivatives, A2A-selective adenosine receptor antagonists. J Med Chem 40:4396–4405PubMedCrossRefGoogle Scholar
  161. Müller CE, Sauer R, Geis U, Frobenius W, Talik P, Pawlowski M (1997b) Aza-analogs of 8-styrylxanthines as A2A-adenosine receptor antagonists. Arch Pharm Pharm Med Chem 330:181–189CrossRefGoogle Scholar
  162. Müller CE, Schobert U, Hipp J, Geis U, Frobenius W, Pawlowski M (1997c) Configurationally stable analogs of styrylxanthines as A2A adenosine receptor antagonist. Eur J Med Chem 32:709–719CrossRefGoogle Scholar
  163. Müller CE, Sandoval-Ramirez J, Schobert U, Geis U, Frobenius W, Klotz KN (1998) 8-(Sulfostyryl)xanthines: water-soluble A2A-selective adenosine receptor antagonists. Bioorg Med Chem 6:707–719PubMedCrossRefGoogle Scholar
  164. Müller CE, Maurinsh J, Sauer R (2000) Binding of [3H]MSX-2 (3-(3-hydroxypropyl)-7-methyl-8-(m-methoxystyryl)-1-propargylxanthine) to rat striatal membranes - a new, selective antagonist radioligand for A2A adenosine receptors. Eur J Pharm Sci 10:259–265PubMedCrossRefGoogle Scholar
  165. Müller CE, Thorand M, Qurishi R, Diekmann M, Jacobson KA, Padgett WL, Daly JW (2002a) Imidazo[2,1-i]purin-5-ones and related tricyclic water-soluble purine derivatives: potent A2A- and A3-adenosine receptor antagonists. J Med Chem 45:3440–3450PubMedCrossRefGoogle Scholar
  166. Müller CE, Diekmann M, Thorand M, Ozola V (2002b) [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 12:501–503PubMedCrossRefGoogle Scholar
  167. Müller CE, Ferré S (2007) Blocking striatal adenosine A2A receptors: a new strategy for basal ganglia disorders. Recent Patents CNS Drug Discov 2:1–21CrossRefGoogle Scholar
  168. Müller CE, Hockemeyer J, Tzvetkov NT, Burbiel JC (2008) Preparation of 8-ethynyl-xanthine derivatives as selective A2A receptor antagonists (SANOL Arznei Schwarz GmbH, Germany). PCT Int Appl; WO 2008077557 A1Google Scholar
  169. Nagel J, Schladebach H, Koch M, Schwienbacher I, Müller CE, Hauber W (2003) Effects of an adenosine A2A receptor blockade in the nucleus accumbens on locomotion, feeding, and prepulse inhibition in rats. Synapse 49:279–286PubMedCrossRefGoogle Scholar
  170. Nieto MI, Balo MC, Brea J, Caamano O, Cadavid MI, Fernandez F, Mera XG, Lopez C, Rodriguez-Borges JE (2009) Synthesis of novel 1-alkyl-8-substituted 3-(3-methoxypropyl)xanthines as putative A2B receptor antagonists. Bioorg Med Chem 17:3426–3432PubMedCrossRefGoogle Scholar
  171. Noguchi J, Ishiwata K, Furuat R, J-i S, Kiyosawa M, Ishii S-i, Endo K, Suzuki F, Senda M (1997) Evaluatioin of carbon-11 labeled KF15372 and its ethyl and methyl derivatives as a potential CNS adenosine A2 receptor ligand. Nucl Med Biol 24:53–59PubMedCrossRefGoogle Scholar
  172. Nonaka Y, Shimada J, Nonaka H, Koike N, Aoki N, Kobayashi H, Kase H, Yamaguchi K, Suzuki F (1993) Photoisomerization of a potent and selective adenosine A2 antagonist, (E)-1,3-dipropyl-8-(3, 4-dimethoxystyryl)-7-methylxanthine. J Med Chem 36:3731–3733PubMedCrossRefGoogle Scholar
  173. Nonaka H, Ichimura M, Takeda M, Nonaka Y, Shimada J, Suzuki F, Yamaguchi K, Kase H (1994a) KF17837 ((E)-8-(3, 4-dimethoxystyryl)-1,3-dipropyl-7-methylxanthine), a potent and selective adenosine A2 receptor antagonist. Eur J Pharmacol 267:335–341PubMedCrossRefGoogle Scholar
  174. Nonaka H, Mori A, Ichimura M, Shindou T, Yanagawa K, Shimada J, Kase H (1994b) Binding of [3H]KF17837S, a selective adenosine A2 receptor antagonist, to rat brain membranes. Mol Pharmacol 46:817–822PubMedGoogle Scholar
  175. Obiefuna PC, Batra VK, Nadeem A, Borron A, Wilson CN, Mustafa SJ (2005) A novel A1 adenosine receptor antagonist, L-97–1 [3-[2-(4-aminophenyl)-ethyl]-8-benzyl-7-{2-ethyl-(2-hydroxy-ethyl)-amino]-ethyl}-1-propyl-3,7-dihydro-purine-2,6-dione], reduces allergic responses to house dust mite in an allergic rabbit model of asthma. J Pharmacol Exp Ther 315:329–336PubMedCrossRefGoogle Scholar
  176. Olah ME, Jacobson KA, Stiles GL (1989) Affinity chromatography of the bovine cerebral cortex A1 adenosine receptor. FEBS Lett 257:292–296PubMedCrossRefGoogle Scholar
  177. Ozola V, Thorand M, Diekmann M, Qurishi R, Schumacher B, Jacobson KA, Müller CE (2003) 2-Phenylimidazo[2,1-i]purin-5-ones: structure-activity relationships and characterization of potent and selective inverse agonists at human A3 adenosine receptors. Bioorg Med Chem 11:347–356PubMedCrossRefGoogle Scholar
  178. Park KS, Hoffmann C, Kim HO, Padgett WL, Daly JW, Brambilla R, Motta C, Abbracchio MP, Jacobson KA (1998) Activation and desensitization of rat A3-adenosine receptors by selective adenosine derivatives and xanthine-7-ribosides. Drug Dev Res 44:97–105CrossRefGoogle Scholar
  179. Pastorin G, Bolcato C, Cacciari B, Kachler S, Klotz K-N, Montopoli C, Moro S, Spalluto G (2005) Synthesis, biological and modelling studies of 1,3-di-n-propyl-2, 4-dioxo-6-methyl-8-(substituted) 1,2,3,4-tetrahydro[1,2,4]triazolo[3,4-f]purines as adenosine receptor antagonists. Farmaco 60:643–651PubMedCrossRefGoogle Scholar
  180. Patel A, Craig RH, Daluge SM, Linden J (1988) 125I-BW-A844U, an antagonist radioligand with high affinity and selectivity for adenosine A1 receptors, and 125I-azido-BW-A844U, a photoaffinity label. Mol Pharmacol 33:585–591PubMedGoogle Scholar
  181. Peet NP, Lentz NL, Dudley MW, Ogden AM, McCarty DR, Racke MM (1993) Xanthines with C8 chiral substituents as potent and selective adenosine A1 antagonists. J Med Chem 36:4015–4020PubMedCrossRefGoogle Scholar
  182. Petzer JP, Steyn S, Castagnoli KP, Chen JF, Schwarzschild MA, Van der Schyf CJ, Castagnoli N (2003) Inhibition of monoamine oxidase B by selective adenosine A2A receptor antagonists. Bioorg Med Chem 11:1299–1310PubMedCrossRefGoogle Scholar
  183. Petzer JP, Castagnoli N Jr, Schwarzschild MA, Chen J-F, Van der Schyf CJ (2009) Dual-target-directed drugs that block monoamine oxidase B and adenosine A2A receptors for Parkinson’s disease. Neurotherapeutics 6:141–151PubMedCrossRefGoogle Scholar
  184. Pfister JR, Belardinelli L, Lee G, Lum RT, Milner P, Stanley WC, Linden J, Baker SP, Schreiner G (1997) Synthesis and biological evaluation of the enantiomers of the potent and selective A1-adenosine antagonist 1,3-dipropyl-8-[2-(5,6-epoxynorbornyl)]xanthine. J Med Chem 40:1773–1778PubMedCrossRefGoogle Scholar
  185. Pretorius J, Malan SF, Castagnoli N Jr, Bergh JJ, Petzer JP (2008) Dual inhibition of monoamine oxidase B and antagonism of the adenosine A2A receptor by (E,E)-8-(4-phenylbutadien-1-yl)caffeine analogues. Bioorg Med Chem 16:8676–8684PubMedCrossRefGoogle Scholar
  186. Priego E-M, von Frijtag Drabbe Kuenzel KJ, IJzerman AP, Camarasa M-J, Pérez-Pérez M-J (2002) Pyrido[2,1-f]purine-2,4-dione derivatives as a novel class of highly potent human A3 adenosine receptor antagonists. J Med Chem 45:3337–3344PubMedCrossRefGoogle Scholar
  187. Priego E-M, Pérez-Pérez M-J, von Frijtag Drabbe Kuenzel JK, de Vries H, IJzerman AP, Camarasa M-J, Martín-Santamaría S (2008) Selective human adenosine A3 antagonists based on pyrido[2,1-f]purine-2,4-diones: novel features of hA3 antagonist binding. ChemMedChem 3:111–119PubMedCrossRefGoogle Scholar
  188. Richardson PJ, Kase H, Jenner PG (1997) Adenosine A2A receptor antagonists as new agents for the treatment of Parkinson's disease. Trends Pharmacol Sci 18:338–344PubMedGoogle Scholar
  189. Robeva AS, Woodard RL, Jin X, Gao Z, Bhattarcharya S, Taylor HE, Rosin DL, Linden J (1996) Molecular characterization of recombinant human adenosine receptors. Drug Dev Res 39:243–252CrossRefGoogle Scholar
  190. Saki M, Tsumuki H, Nonaka H, Shimada J, Ichimura M (2002) KF26777 (2-(4-bromophenyl)-7,8-dihydro-4-propyl-1H-imidazo[2,1-i]purin-5(4H)-one dihydrochloride), a new potent and selective adenosine A3 receptor antagonist. Eur J Pharmacol 444:133–141PubMedCrossRefGoogle Scholar
  191. Salamone JD, Betz AJ, Ishiwari K, Felsted J, Madson L, Mirante B, Clark K, Font L, Korbey S, Sager TN, Hockemeyer J, Müller CE (2008a) Tremorolytic effects of adenosine A2A antagonists: implications for parkinsonism. Front Biosci 13:3594–3605PubMedCrossRefGoogle Scholar
  192. Salamone JD, Ishiwari K, Betz AJ, Farrar AM, Mingote SM, Font L, Hockemeyer J, Müller CE, Correa M (2008b) Dopamine/adenosine interactions related to locomotion and tremor in animal models: possible relevance to parkinsonism. Parkinsonism Relat Disord 14(Suppl 2):S130–134PubMedCrossRefGoogle Scholar
  193. Salvatore CA, Jacobson MA, Taylor HE, Linden J, Johnson RG (1993) Molecular cloning and characterization of the human A3 adenosine receptor. Proc Natl Acad Sci USA 90:10365–10369PubMedCrossRefGoogle Scholar
  194. Sauer R, Maurinsh J, Reith U, Fülle F, Klotz KN, Müller CE (2000) Water-soluble phosphate prodrugs of 1-propargyl-8-styrylxanthine derivatives, A2A-selective adenosine receptor antagonists. J Med Chem 43:440–448PubMedCrossRefGoogle Scholar
  195. Scammels PJ, Baker SP, Belardinelli L, Olsson RA (1994) Substituted 1,3-dipropylxanthines as irreversible antagonists of A1 adenosine receptors. J Med Chem 37:2704–2712CrossRefGoogle Scholar
  196. Schapira AH, Bezard E, Brotchie J, Calon F, Collingridge GL, Ferger B, Hengerer B, Hirsch E, Jenner P, Le Novere N, Obeso JA, Schwarzschild MA, Spampinato U, Davidai G (2006) Novel pharmacological targets for the treatment of Parkinson's disease. Nat Rev Drug Discov 5:845–854PubMedCrossRefGoogle Scholar
  197. Schindler CW, Karcz-Kubicha M, Thorndike EB, Müller CE, Tella SR, Goldberg SR, Ferré S (2004) Lack of adenosine A1 and dopamine D2 receptor-mediated modulation oft he cardiovascular effects oft he adenosine A2A receptor agonist CGS 21680. Eur J Pharmacol 484:269–275PubMedCrossRefGoogle Scholar
  198. Schindler CW, Karcz-Kubicha M, Thorndike EB, Müller CE, Tella SR, Ferré S, Goldberg SR (2005) Role of central and peripheral adenosine recepotrs in the cardiovascular responses to intraperitoneal injections of adenosine A1 and A2A subtype receptor agonists. Br J Pharmacol 144:642–650PubMedCrossRefGoogle Scholar
  199. Schingnitz G, Küfner-Mühl U, Ensinger H, Lehr E, Kuhn FJ (1991) Selective A1 antagonists for treatment of cognitive deficits. Nucleosides Nucleotides 10:1067–1076CrossRefGoogle Scholar
  200. Schwarzschild MA, Agnati L, Fuxe K, Chen JF, Morelli M (2006) Targeting adenosine A2A receptors in Parkinson’s disease. Trends Neurosci 29:647–654PubMedCrossRefGoogle Scholar
  201. Seale TW, Abla KA, Shamim MT, Carney JM, Daly JW (1988) 3,7-Dimethyl-1-propargylxanthine: a potent and selective in vivo antagonist of adenosine analogs. Life Sci 43:1671–1684PubMedCrossRefGoogle Scholar
  202. Shamim MT, Ukena D, Padgett WL, Hong O, Daly JW (1988) 8-Aryl and 8-cycloalkyl-1,3-dipropylxanthines: further potent and selective antagonists for A1-adenosine receptors. J Med Chem 31:613–617PubMedCrossRefGoogle Scholar
  203. Shamim MT, Ukena D, Padgett WL, Daly JW (1989) Effects of 8-phenyl and 8-cycloalkyl substituents on the activity of mono-, di-, and trisubstituted alkylxanthines with substitution at the 1-, 3-, and 7-positions. J Med Chem 32:1231–1237PubMedCrossRefGoogle Scholar
  204. Shimada J, Suzuki F, Nonaka H, Ishii A (1992) 8-Polycycloalkyl-1,3-dipropylxanthines as potent and selective antagonists for A1-adenosine receptors. J Med Chem 35:924–930PubMedCrossRefGoogle Scholar
  205. Shimada J, Koike N, Nonaka H, Shiozaki S, Yanagawa K, Kanda T, Kobayashi H, Ichimura M, Nakamura J, Kase H, Suzuki F (1997) Adenosine A2A antagonists with potent anti-cataleptic activity. Bioorg Med Chem Lett 7:2349–2352CrossRefGoogle Scholar
  206. Shukla D, Chakraborty S, Singh S, Mishra B (2009) Doxofylline: a promising methylxanthine derivative for the treatment of asthma and chronic obstructive pulmonary disease. Expert Opin Pharmacother 10:2343–2356PubMedCrossRefGoogle Scholar
  207. Slawsky MT, Givertz MM (2009) Rolofylline: a selective adenosine 1 receptor antagonist fort he treatment of heart failure. Expert Opin Pharmacother 10:311–322PubMedCrossRefGoogle Scholar
  208. Solinas M, Ferré S, Antoniou K, Quarta D, Zustinova Z, Pappas HJ, LA SPN, Wertheim C, Müller CE, Goldberg SR (2005) Involvement of adenosine A1 receptors in the discriminative-stimulus effects of caffeine in rats. Psychopharmacology 179:576–586PubMedCrossRefGoogle Scholar
  209. Sorbera LA, Martín L, Castaner J (2000) Drugs Future 25:1011–1016CrossRefGoogle Scholar
  210. Soriano A, Ventura R, Molero A, Hoen R, Casadó V, Cortés A, Fanelli F, Albericio F, Lluís C, Franco R, Royo M (2009) Adenosine A2A receptor-antagonist/dopamine D2 receptor agonist bivalent ligands as pharmacological tools to detect A2A-D2 receptor heteromers. J Med Chem 52:5590–5602PubMedCrossRefGoogle Scholar
  211. Stefanachi A, Brea JM, Cadavid MI, Centeno NB, Esteve C, Loza MI, Martinez A, Nieto R, Ravina E, Sanz F, Segarra V, Sotelo E, Vidal B, Carotti A (2008) 1-, 3- and 8-Substituted 9-deazaxanthines as potent and selective antagonists at the human A2B adenosine receptor. Bioorg Med Chem 16:2852–2869PubMedCrossRefGoogle Scholar
  212. Stefanovich V (1989) The xanthines. Drug News Perspect 2:82–88Google Scholar
  213. Stiles GL, Jacobson KA (1987) A new high affinity, iodinated adenosine receptor antagonist as a radioligand/photoaffinity crosslinking probe. Mol Pharmacol 32:184–188PubMedGoogle Scholar
  214. Stiles GL, Jacobson KA (1988) High affinity acylating antagonists for the A1 adenosine receptor: identification of binding subunit. Mol Pharmacol 34:724–728PubMedGoogle Scholar
  215. Stone GA, Jarvis MF, Sills M, Weeks B, Snowhill EW, Williams M (1988) Species differences in high affinity adenosine A2 receptors in striatal membranes from mammalian brain. Drug Dev Res 15:31–46CrossRefGoogle Scholar
  216. Strömberg I, Popoli P, Müller CE, Ferré S, Fuxe K (2000) Electrophysiological and behavioural evidence for an antagonistic modulatory role of adenosine A2A receptors in dopamine D2 receptor regulation in the rat dopamine denervated striatum. Eur J Neurosci 12:4033–4037PubMedCrossRefGoogle Scholar
  217. Suzuki F, Shimada J, Mizumoto H, Karasawa A, Kubo K, Nonaka H, Ishii A, Kawakita T (1992a) Adenosine A1 antagonists. 2. Structure-activity relationships on diuretic activities and protective effects against acute renal failure. J Med Chem 35:3066–3075PubMedCrossRefGoogle Scholar
  218. Suzuki F, Shimada J, Nonaka H, Ishii A, Shiozaki S, Ichikawa S, Ono E (1992b) 7, 8-Dihydro-8-ethyl-2-(3-noradamantyl)-4-propyl-1H-imidazo[2,1-i]purin-5(4H)-one: a potent and water-soluble adenosine A1 antagonist. J Med Chem 35:3578–3581PubMedCrossRefGoogle Scholar
  219. Takahashi RN, Pamplona FA, Prediger RD (2008) Adenosine receptor antagonists for cognitive dysfunction: a review of animal studies. Front Biosci 13:2614–2632PubMedCrossRefGoogle Scholar
  220. Thorsell A, Johnson J, Heilig M (2007) Effect of the adenosine A2A receptor antagonist 3,7-dimethyl-propargylxanthine on anxiety-like and depression-like behavior and alcohol consumption in Wistar rats. Alcohol Clin Exp Res 31:1302–1307PubMedCrossRefGoogle Scholar
  221. Ukena D, Jacobson KA, Kirk KL, Daly JW (1986a) A [3H]amine congener of 1,3-dipropyl-8-phenylxanthine. A new radioligand for A2 adenosine receptors of human platelets. FEBS Lett 199:269–274PubMedCrossRefGoogle Scholar
  222. Ukena D, Jacobson KA, Padgett WL, Ayala C, Shamim MT, Kirk KL, Olsson RA, Daly JW (1986b) Species differences in structure-activity relationships of adenosine agonists and xanthine antagonists at brain A1 adenosine receptors. FEBS Lett 209:122–128PubMedCrossRefGoogle Scholar
  223. Ukena D, Daly JW, Kirk KL, Jacobson KA (1986c) Functionalized congeners of 1,3-dipropyl-8-phenylxanthine: potent antagonists for adenosine receptors that modulate membrane adenylate cyclase in pheochromocytoma cells, platelets and fat cells. Life Sci 38:797–807PubMedCrossRefGoogle Scholar
  224. Ukena D, Schudt C, Sybrecht GW (1993) Adenosine receptor-blocking xanthines as inhibitors of phosphodiesterase isozymes. Biochem Pharmacol 45:847–851PubMedCrossRefGoogle Scholar
  225. van den Berg D, Zoellner KR, Ogunrombi MO, Malan SF, Terre'Blanche G, Castagnoli N Jr, Bergh JJ, Petzer JP (2007) Inhibition of monoamine oxidase B by selected benzimidazole and caffeine analogues. Bioorg Med Chem 15:3692–3702PubMedCrossRefGoogle Scholar
  226. van Galen PJM, van Bergen AH, Gallo-Rodriguez C, Melman N, Olah ME, IJzerman AP, Stiles GL, Jacobson KA (1994) A binding site model and structure-activity relationships for the rat A3 adenosine receptor. Mol Pharmacol 45:1101–1111PubMedGoogle Scholar
  227. van Muijlwijk-Koezen JE, Timmerman H, van der Sluis RP, van de Stolpe AC, Menge WM, Beukers MW, van der Graaf PH, de Groote M, IJzerman AP (2001) Synthesis and use of FSCPX, an irreversible adenosine A1 antagonist, as a ‘receptor knock-down’ tool. Bioorg Med Chem 11:815–818CrossRefGoogle Scholar
  228. Vlok N, Malan SF, Castagnoli N Jr, Bergh JJ, Petzer JP (2006) Inhibition of monoamine oxidase B by analogues of the adenosine A2A receptor antagonist (E)-8-(3-chlorostyryl)caffeine (CSC). Bioorg Med Chem 14:3512–2351PubMedCrossRefGoogle Scholar
  229. Vollmann K, Qurishi R, Hockemeyer J, Müller CE (2008) Synthesis and properties of a new water-soluble prodrug of the adenosine A2A receptor antagonist MSX-2. Molecules 13:348–359PubMedCrossRefGoogle Scholar
  230. Vu CB (2005) Recent advances in the design and optimization of adenosine A2A receptor antagonists. Curr Opin Drug Discov Dev 8:458–468Google Scholar
  231. Vu CB, Kiesman WF, Conlon PR, Lin K-C, Tam M, Petter RC, Smits G, Lutterodt F, Jin X, Chen L (2006) Zhang J (2006) Tricyclic imidazoline derivatives as potent and selective adenosine A1 receptor antagonists. J Med Chem 49:7132–7139PubMedCrossRefGoogle Scholar
  232. Weiss HM, Grisshammer R (2002) Purification and characterization of the human adenosine A2a receptor functionally expressed in Escherichia coli. Eur J Biochem 269:82–92PubMedCrossRefGoogle Scholar
  233. Weyler S, Fülle F, Diekmann M, Schumacher B, Hinz S, Klotz KN, Müller CE (2006) Improving potency, selectivity, and water-solubility of adenosine A1 receptor antagonists: xanthines modified at position 3 and related pyrimido[1,2,3-cd]purinediones. ChemMedChem 1:891–902PubMedCrossRefGoogle Scholar
  234. Worden L, Shahriari M, Farrar A, Sink KS, Hockemeyer J, Müller CE, Salamone JD (2009) The adenosine A2A antagonist MSX-3 reverses the effort-related effects of dopamine blockade: differential interaction with D1 and D2 family antagonists. Psychopharmacology 203:489–499PubMedCrossRefGoogle Scholar
  235. Yan L, Müller CE (2004) Preparation, properties, reactions, and adenosine receptor affinities of sulfophenylxanthine nitrophenyl esters: toward the development of sulfonic acid prodrugs with peroral bioavailability. J Med Chem 47:1031–1043PubMedCrossRefGoogle Scholar
  236. Yan L, Bertarelli CG, Hayallah AM, Meyer H, Klotz KN, Müller CE (2006) A new synthesis of sulfonamides by aminolysis of p-nitrophenylsulfonates yielding potent and selective adenosine A2B receptor antagonists. J Med Chem 49:4384–4391PubMedCrossRefGoogle Scholar
  237. Yu L, Shen HY, Coelho JE, Araujo IM, Huang QY, Day YJ, Rebola N, Canas PM, Rapp EK, Ferrara J, Taylor D, Müller CE, Linden J, Cunha RA, Chen JF (2008) Adenosine A2A receptor antagonists exert motor and neuroprotective effects by distinct cellular mechanisms. Ann Neurol 63:338–346PubMedCrossRefGoogle Scholar
  238. Yuzlenko O, Kiec-Kononowicz K (2006) Potent adenosine A1 and A2A receptors antagonists: recent developments. Curr Med Chem 13:3609–3625PubMedCrossRefGoogle Scholar
  239. Zablocki J, Kalla R, Perry T, Palle V, Varkhedkar V, Xiao D, Piscopio A, Maa T, Gimbel A, Hao J, Chu N, Leung K, Zeng D (2005) The discovery of a selective, high affinity A2B adenosine receptor antagonist for the potential treatment of asthma. Bioorg Med Chem 15:609–612CrossRefGoogle Scholar

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© Springer Berlin Heidelberg 2011

Authors and Affiliations

  1. 1.PharmaCenter Bonn, Pharmaceutical Sciences Bonn (PSB)University of Bonn, Pharmaceutical InstituteBonnGermany
  2. 2.Molecular Recognition Section, Laboratory of Bioorganic Chemistry, National Institute of Diabetes and Digestive and Kidney DiseasesNational Institutes of HealthBethesdaUSA

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