Skip to main content
SpringerLink
Log in

Recent improvements in the development of A2B adenosine receptor agonists

  • Review
  • Published:
Purinergic Signalling Aims and scope Submit manuscript

Abstract

Adenosine is known to exert most of its physiological functions by acting as local modulator at four receptor subtypes named A1, A2A, A2B and A3 (ARs). Principally as a result of the difficulty in identifying potent and selective agonists, the A2B AR is the least extensively characterised of the adenosine receptors family. Despite these limitations, growing understanding of the physiological meaning of this target indicates promising therapeutic perspectives for specific ligands. As A2B AR signalling seems to be associated with pre/postconditioning cardioprotective and anti-inflammatory mechanisms, selective agonists may represent a new therapeutic group for patients suffering from coronary artery disease. Herein we present an overview of the recent advancements in identifying potent and selective A2B AR agonists reported in scientific and patent literature. These compounds can be classified into adenosine-like and nonadenosine ligands. Nucleoside-based agonists are the result of modifying adenosine by substitution at the N 6-, C2-positions of the purine heterocycle and/or at the 5′-position of the ribose moiety or combinations of these substitutions. Compounds 1-deoxy-1-{6-[N′-(furan-2-carbonyl)-hydrazino]-9H-purin-9-yl}-N-ethyl-β-D-ribofuranuronamide (19, hA1 K i = 1050 nM, hA2A K i = 1550 nM, hA2B EC50 = 82 nM, hA3 K i > 5 μM) and its 2-chloro analogue 23 (hA1 K i = 3500 nM, hA2A K i = 4950 nM, hA2B EC50 = 210 nM, hA3 K i > 5 μM) were confirmed to be potent and selective full agonists in a cyclic adenosine monophosphate (cAMP) functional assay in Chinese hamster ovary (CHO) cells expressing hA2B AR. Nonribose ligands are represented by conveniently substituted dicarbonitrilepyridines, among which 2-[6-amino-3,5-dicyano-4-[4-(cyclopropylmethoxy)phenyl]pyridin-2-ylsulfanyl]acetamide (BAY-60–6583, hA1, hA2A, hA3 EC50 > 10 μM; hA2B EC50 = 3 nM) is currently under preclinical-phase investigation for treating coronary artery disorders and atherosclerosis.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4

Similar content being viewed by others

Abbreviations

ABOPX:

3-(3,4-aminobenzyl)-8-(4-oxyacetate)phenyl-1-propyl-xanthine

ADP:

Adenosine Diphosphate

Ars:

Adenosine Receptors

ASMCs:

Arterial Smooth Muscle Cells

ATP:

Adenosine Triphosphate

BAY 60–6583:

2-[6-amino-3,5-dicyano-4-(4-hydroxyphenyl)pyridin-2-ylsulfanyl]acetamide

cAMP:

cyclic Adenosine Monophosphate

[3H]CCPA:

[3H]-2-chloro-N 6-cyclopentyladenosine

CFTR:

Cystic Fibrosis Transmembrane Conductance Regulator

CGS21680:

2-([4-(2-carboxyethyl)phenylethyl]amino)-5′-N-ethylcarboxamidoadenosine

CHO cells:

Chinese Hamster Ovary cells

CNS:

Central Nervous System

COPD:

Chronic Obstructive Pulmonary Disease

DPCPX:

1,3-dipropyl-8-cyclopentyl-xanthine

FAD:

Flavin Adenine Dinucleotide

GMCs:

Glomerular Mesangial Cells

[3H]-CHA:

[3H]N 6-cyclohexyladenosine

HEK293 cells:

Human Embryonic Kidney cells

[125I]-AB-MECA:

[125I]N 6-(4-amino-3-iodobenzyl)adenosine-5′-N-methyl-uronamide

[125I]APNEA:

[125I]N 6–2-(4-amino-phenyl)ethyladenosine

IB-MECA:

N6-(3-iodo-benzyl) adenosine-5′-N-methyluronamide

IL:

Interleukin

IPC:

Ischemic Preconditioning

MAPK:

Mitogen-Activated Protein Kinase

MRE 2029-F20:

N-benzo[1,3]dioxol-5-yl-2-[5-(1,3-dipropyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl)-1-methyl-1H-pyrazol-3-yloxy]-acetamide

MRS 1754:

[N-(4-cyanophenyl)-2-[4-(2,3,6,7-tetrahydro-2,6-dioxo-1,3-dipropyl-1H-purin-8-yl)-phenoxy]acetamide

NAD:

Nicotinamide Adenine Dinucleotide

NECA:

5′-N-ethylcarboxamidoadenosine

NO:

Nitric Oxide

OSIP339391:

N-(2-(2-Phenyl-6-[4-(2,2,3,3-tetratritrio-3-phenylpropyl)-piperazine-1-carbonyl]-7Hpyrrolo[2,3-d]pyrimidin-4-ylamino)-ethyl)-acetamide

PHPAdo:

2-phenylhydroxypropynyladenosine

PHPNECA:

2-phenylhydroxypropynyl-5′-N-ethylcarboxamidoadenosine

R-PIA:

N6-(R)-phenylisopropyladenosine

SAM:

S-Adenosyl-L-Methionine

TNFα:

Tumor Necrosis Factor α

ZM 241385:

(4-(2-[7-amino-2-(2-furyl)-[1,2,4]triazolo-[2,3-a][1,3,5]triazin-5-ylamino] ethyl)-phenol

References

  1. Fredholm BB, Dunwiddie TV (1988) How does adenosine inhibit transmitter release? Trends Pharmacol Sci 9:130–134

    Article  PubMed  CAS  Google Scholar 

  2. Ohta A, Sitkovsky M (2001) Role of G-protein-coupled adenosine receptors in downregulation of inflammation and protection from tissue damage. Nature 414:916–920

    Article  PubMed  CAS  Google Scholar 

  3. Forman MB, Stone GW, Jackson EK (2006) Role of adenosine as adjunctive therapy in acute myocardial infarction. Cardiovasc Drug Rev 24:116–147

    Article  PubMed  CAS  Google Scholar 

  4. Dare E, Schulte G, Karovic O et al (2007) Modulation of glial cell functions by adenosine receptors. Physiol Behav 92:15–20

    Article  PubMed  CAS  Google Scholar 

  5. Burnstock G (2007) Physiology and pathophysiology of purinergic neurotransmission. Physiol Rev 87:659–797

    Article  PubMed  CAS  Google Scholar 

  6. Burnstock G (2007) Purine and pyrimidine receptors. Cell Mol Life Sci 64:1471–1483

    Article  PubMed  CAS  Google Scholar 

  7. Fredholm BB (2007) Adenosine, an endogenous distress signal, modulates tissue damage and repair. Cell Death Differ 14:1315–1323

    Article  PubMed  CAS  Google Scholar 

  8. Sawynok J (2007) Adenosine and ATP receptors. Handb Exp Pharmacol 177(Analgesia):309–328

    PubMed  CAS  Google Scholar 

  9. McGaraughty S, Jarvis MF (2006) Purinergic control of neuropathic pain. Drug Dev Res 67:376–388

    Article  CAS  Google Scholar 

  10. Fredholm BB, Arslan G, Halldner L et al (2000) Structure and function of adenosine receptors and their genes. Naunyn Schmiedebergs Arch Pharmacol 362:364–374

    Article  PubMed  CAS  Google Scholar 

  11. Klotz KN (2000) Adenosine receptors and their ligands. Naunyn Schmiedebergs Arch Pharmacol 362:382–391

    Article  PubMed  CAS  Google Scholar 

  12. Fredholm BB, IJzerman AP, Jacobson KA, International Union of Pharmacology XXV et al (2001) Nomenclature and classification of adenosine receptors. Pharmacol Rev 53:527–552

    PubMed  CAS  Google Scholar 

  13. Klinger M, Freissmuth M, Nanoff C (2002) Adenosine receptors: G protein-mediated signalling and the role of accessory proteins. Cel Signal 14:99–108

    Article  CAS  Google Scholar 

  14. Feoktistov I, Biaggioni I (1997) Adenosine A2B receptors. Pharmacol Rev 49:381–402

    PubMed  CAS  Google Scholar 

  15. Beukers MW, Den Dulk H, Van Tilburg EW et al (2000) Why are A2B receptors low-affinity adenosine receptors? mutation of Asn273 to Tyr increases affinity of human A2B receptor for 2-(1-hexynyl)adenosine. Mol Pharmacol 58:1349–1356

    PubMed  CAS  Google Scholar 

  16. Gessi S, Varani K, Merighi S et al (2006) Novel selective antagonist radioligands for the pharmacological study of A2B adenosine receptors. Purinergic Signal 2:583–588

    Article  PubMed  CAS  Google Scholar 

  17. Ji X, Kim YC, Ahern DG et al (2001) [3H]MRS 1754, a selective antagonist radioligand for A2B adenosine receptors. Biochem Pharmacol 61:657–663

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  19. Baraldi PG, Tabrizi MA, Preti D et al (2004) [3H]-MRE 2029-F20, a selective antagonist radioligand for the human A2B adenosine receptors. Bioorg Med Chem Lett 14:3607–3610

    Article  PubMed  CAS  Google Scholar 

  20. Grenz A, Zhang H, Weingart J et al (2007) Lack of effect of extracellular adenosine generation and signaling on renal erythropoietin secretion during hypoxia. Am J Physiol 293(5, Pt. 2):F1501–F1511

    Article  CAS  Google Scholar 

  21. Allaman I, Lengacher S, Magistretti PJ et al (2003) A2B receptor activation promotes glycogen synthesis in astrocytes through the modulation of gene expression. Am J Physiol Cell Physiol 284(3, Pt.1):C696–C704

    PubMed  CAS  Google Scholar 

  22. Yaar R, Jones MR, Chen J-F et al (2004) Animal models for the study of adenosine receptor function. J Cell Physiol 202:9–20

    Article  CAS  Google Scholar 

  23. Eckle O, Krahn T, Grenz A et al (2007) Cardioprotection by Ecto-5′-Nucleotidase (CD73) and A2B adenosine receptors. Circulation 115:1581–1590

    Article  PubMed  CAS  Google Scholar 

  24. Feoktistov I, Ryzhov S, Goldstein AE et al (2003) Mast cell-mediated stimulation of angiogenesis. Circ Res 92:485–492

    Article  PubMed  CAS  Google Scholar 

  25. Feoktistov I, Ryzhov S, Zhong H et al (2004) Hypoxia modulates adenosine receptors in human endothelial and smooth muscle cells toward an A2B angiogenic phenotype. Hypertension 44:649–654

    Article  PubMed  CAS  Google Scholar 

  26. Eltzschig HK, Ibla JC, Furuta GT et al (2003) Coordinated adenine nucleotide phosphohydrolysis and nucleoside signaling in posthypoxic endothelium: Role of ectonucleotidases and adenosine A2B receptors. J Exp Med 198:783–796

    Article  PubMed  CAS  Google Scholar 

  27. Pierson PM, Peteri-Brunbaeck B, Pisani DF et al (2007) A2B receptor mediates adenosine inhibition of taurine efflux from pituicytes. Biol Cell 99:445–454

    Article  PubMed  CAS  Google Scholar 

  28. Panjehpour M, Castro M, Klotz K-N (2005) Human breast cancer cell line MDA-MB-231 expresses endogenous A2B adenosine receptors mediating a Ca2+ signal. Br J Pharmacol 145:211–218

    Article  PubMed  CAS  Google Scholar 

  29. Strohmeier GR, Reppert SM, Lencer WI et al (1995) The A2B adenosine receptor mediates cAMP responses to adenosine receptor agonists in human intestinal epithelia. J Biol Chem 270:2387–2394

    Article  PubMed  CAS  Google Scholar 

  30. Lazarowski ER, Mason SJ, Clarke L et al (1992) Adenosine receptors on human airway epithelia and their relationship to chloride secretion. Br J Pharmacol 106:774–782

    PubMed  CAS  Google Scholar 

  31. Huang P, Lazarowski ER, Tarran R et al (2001) Compartmentalized autocrine signaling to cystic fibrosis transmembrane conductance regulator at the apical membrane of airway epithelial cells. Proc Natl Acad Sci USA 98:14120–14125

    Article  PubMed  CAS  Google Scholar 

  32. Spicuzza L, Di Maria G, Polosa R (2006) Adenosine in the airways: Implications and applications. Eur J Pharmacol 533:77–88

    Article  PubMed  CAS  Google Scholar 

  33. Ryzhov S, Goldstein AE, Matafonov A et al (2004) 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

    PubMed  CAS  Google Scholar 

  34. Baraldi PG, Fruttarolo F, Tabrizi MA et al (2007) Novel 8-heterocyclyl xanthine derivatives in drug development-an update. Expert Opin Drug Discov 2:1153–1159

    Article  Google Scholar 

  35. Fozard JR, McCarthy C (2002) Adenosine receptor ligands as potential therapeutics in asthma. Curr Opin Investig Drugs 3:69–77

    PubMed  CAS  Google Scholar 

  36. Zhong H, Belardinelli L, Maa T et al (2004) A2B adenosine receptors increase cytokine release by bronchial smooth muscle cells. Am J Respir Cell Mol Biol 30:118–125

    Article  PubMed  CAS  Google Scholar 

  37. Rorke S, Holgate ST (2002) Targeting adenosine receptors: novel therapeutic targets in asthma and chronic obstructive pulmonary disease. Am J Respir Med 1:99–105

    PubMed  CAS  Google Scholar 

  38. Jacobson KA, Gao Z (2006) Adenosine receptors as therapeutic targets. Nat Rev 5:247–264

    CAS  Google Scholar 

  39. Harada H, Asano O, Hoshino Y et al (2001) 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

    Article  PubMed  CAS  Google Scholar 

  40. Grant MB, Davis MI, Caballero S, Feoktistov I, Biaggioni I, Belardinelli L (2001) Proliferation, migration, and ERK activation in human retinal endothelial cells through A2B adenosine receptor stimulation. Invest Ophthalmol Vis Sci 42:2068–2073

    PubMed  CAS  Google Scholar 

  41. Abo-Salem OM, Hayallah AM, Bilkei-Gorzo A et al (2004) Antinociceptive effects of novel A2B adenosine receptor antagonists. J Pharmacol Exp Ther 308:358–366

    Article  PubMed  CAS  Google Scholar 

  42. Clancy JP, Ruiz FE, Sorscher EJ (1999) Adenosine and its nucleotides activate wild-type and R117H CFTR through an A2B receptor-coupled pathway. Am J Physiol 276:C361–C369

    PubMed  CAS  Google Scholar 

  43. Wang L, Kolachala V, Walia B et al (2004) Agonist-induced polarized trafficking and surface expression of the adenosine 2b receptor in intestinal epithelial cells: Role of SNARE proteins. Am J Physiol 287:G1100–G1107

    CAS  Google Scholar 

  44. Lazarowski ER, Tarran R, Grubb BR et al (2004) Nucleotide release provides a mechanism for airway surface liquid homeostasis. J Biol Chem 279:36855–36864

    Article  PubMed  CAS  Google Scholar 

  45. Rosentreter U, Henning R, Bauser M et al (2001) Substituted 2-thio-3,5-dicyano-4-aryl-6-aminopyridines and the use thereof. WO Patent 2001025210

  46. Kuno A, Critz SD, Cui L et al (2007) Protein kinase C protects preconditioned rabbit hearts by increasing sensitivity of adenosine A2B-dependent signaling during early reperfusion. J Mol Cell Cardiol 43:262–271

    Article  PubMed  CAS  Google Scholar 

  47. Philipp S, Yang XM, Cui L et al (2006) Postconditioning protects rabbit hearts through a protein kinase C-adenosine A2B receptor cascade. Cardiovasc Res 70:308–314

    Article  PubMed  CAS  Google Scholar 

  48. Gao Z-G, Jacobson KA (2007) Emerging adenosine receptor agonists. Expert Opin Emerg Drugs 12:479–492

    Article  PubMed  CAS  Google Scholar 

  49. Yang D, Zhan Y, Nguyen HG, Koupenova et al (2006) The A2B adenosine receptor protects against inflammation and excessive vascular adhesion. J Clin Invest 116:1913–1923

    Article  PubMed  CAS  Google Scholar 

  50. Németh ZH, Lutz CS, Csóka B et al (2005) Adenosine augments IL-10 production by macrophages through an A2B receptor-mediated posttranscriptional mechanism. J Immunol 175:8260–8270

    PubMed  Google Scholar 

  51. Hinschen AK, Rose’Meyer RB, Headrick JP (2003) Adenosine receptor subtypes mediating coronary vasodilation in rat hearts. J Cardiovasc Pharmacol 41:73–80

    Article  PubMed  CAS  Google Scholar 

  52. Ansari HR, Nadeem A, Talukder MAH et al (2007) Evidence for the involvement of nitric oxide in A2B receptor-mediated vasorelaxation of mouse aorta. Am J Physiol Heart Circ Physiol 292:H719–H725

    Article  PubMed  CAS  Google Scholar 

  53. Kemp BK, Cocks TM (1999) Adenosine mediates relaxation of human small resistance-like coronary arteries via A2B receptors. Br J Pharmacol 126:1796–1800

    Article  PubMed  CAS  Google Scholar 

  54. Dubey RK, Gillespie DG, Mi Z et al (1998) Adenosine inhibits growth of human aortic smooth muscle cells via A2B receptors. Hypertension 31:516–521

    PubMed  CAS  Google Scholar 

  55. Peyot M-L, Gadeau A-P, Dandré F et al (2000) Extracellular adenosine induces apoptosis of human arterial smooth muscle cells via A2B-purinoceptor. Circ Res 86:76–85

    PubMed  CAS  Google Scholar 

  56. Dubey RK, Gillespie DG, Mi Z et al (2005) Adenosine inhibits PDGF-induced growth of human glomerular mesangial cells via A2B receptors. Hypertension 46:628–634

    Article  PubMed  CAS  Google Scholar 

  57. Iino M, Ehama R, Nakazawa Y et al (2007) Adenosine stimulates fibroblast growth factor-7 gene expression via adenosine A2B receptor signaling in dermal papilla cells. J Investi Dermatol 127:1318–1325

    Article  CAS  Google Scholar 

  58. Tostes RC, Giachini FRC, Carneiro FS et al (2007) Determination of adenosine effects and adenosine receptors in murine corpus cavernosum. J Pharmacol Exp Ther 322:678–685

    Article  PubMed  CAS  Google Scholar 

  59. Faria M, Magalhães-Cardoso T, Lafuente-de-Carvalho J-M et al (2006) Corpus cavernosum from men with vasculogenic impotence is partially resistant to adenosine relaxation due to endothelial A2B receptor dysfunction. J Pharmacol Exp Ther 319:405–413

    Article  PubMed  CAS  Google Scholar 

  60. Le Vraux V, Chen YL, Masson I et al (1993) Inhibition of human monocyte TNF production by adenosine receptor agonists. Life Sci 52:1917–1924

    Article  PubMed  Google Scholar 

  61. Kreckler LM, Wan TC, Ge Z-D et al (2006) Adenosine inhibits tumor necrosis factor-a release from mouse peritoneal macrophages via A2A and A2B but not the A3 adenosine receptor. J Pharmacol Exp Ther 317:172–180

    Article  PubMed  CAS  Google Scholar 

  62. Volpini R, Costanzi S, Vittori S et al (2003) Medicinal chemistry and pharmacology of A2B adenosine receptors. Curr Top Med Chem 3:427–443

    Article  PubMed  CAS  Google Scholar 

  63. Beukers MW, Meurs I, IJzerman AP (2006) Structure-affinity relationships of adenosine A2B receptor ligands. Med Res Rew 26:667–698

    CAS  Google Scholar 

  64. Baraldi PG, Romagnoli R, Preti D et al (2006) Ligands for A2B adenosine receptor subtype. Curr Med Chem 13:3467–3482

    Article  PubMed  CAS  Google Scholar 

  65. De Zwart M, Link R, Von Frijtag Drabbe Künzel JK et al (1998) A functional screening of adenosine analogues at the adenosine A2B receptor: a search for potent agonists. Nucleos Nucleot 17:969–985

    Article  Google Scholar 

  66. De Zwart M, Kourounakis A, Kooijman H et al (1999) 5′-N-substituted carboxamidoadenosines as agonists for adenosine receptors. J Med Chem 42:1384–1392

    Article  PubMed  Google Scholar 

  67. De Zwart M, De Groote M, Van Der Klein PAM et al (2000) Phenyl-substituted N 6-phenyladenosines and N 6-phenyl-5′-N ethylcarboxamidoadenosines with high activity at human adenosine A2B receptors. Drug Dev Res 49:85–93

    Article  Google Scholar 

  68. Jacobson KA, Ohno M, Duong HT et al (2005) A Neoceptor approach to unraveling microscopic interactions between the human A2A adenosine receptor and its agonists. Chem Biol 12:237–247

    Article  PubMed  CAS  Google Scholar 

  69. Baraldi PG, Preti D, Tabrizi MA et al (2007) N 6-[(Hetero)aryl/(cyclo)alkyl-carbamoyl-methoxy-phenyl]-(2-chloro)-5′-N-ethylcarboxamido-adenosines: the first example of adenosine-related structures with potent agonist activity at the human A2B adenosine receptor. Bioorg Med Chem 15:2514–2527

    Article  PubMed  CAS  Google Scholar 

  70. Kim SA, Marshall MA, Melman N et al (2002) Structure-activity relationships at the human and rat A2B adenosine receptors of xanthine derivatives substituted at the 1-, 3-, 7-, and 8-positions. J Med Chem 45:2131–2138

    Article  PubMed  CAS  Google Scholar 

  71. Kim Y-C, Ji X, Melman N et al (2000) Anilide derivatives of an 8-phenylxanthine carboxylic congener are highly potent and selective antagonists at human A2B adenosine receptors. J Med Chem 43:1165–1172

    Article  PubMed  CAS  Google Scholar 

  72. Baraldi PG, Tabrizi MA, Preti D et al (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 47:1434–1447

    Article  PubMed  CAS  Google Scholar 

  73. Ivanov AA, Baskin II, Palyulin VA et al (2002) Molecular modelling of the human A2B adenosine receptor and an analysis of the binding modes of its selective ligands. Mendeleev Commun 6:211–212

    Article  CAS  Google Scholar 

  74. Vittori S, Costanzi S, Lambertucci C et al (2004) A2B adenosine receptor agonists: synthesis and biological evaluation of 2-phenylhydroxypropynyl adenosine and NECA derivatives. Nucleos Nucleot Nucl 23:471–481

    Article  CAS  Google Scholar 

  75. Jacobson MA (2002) Adenosine receptor agonists. Expert Opin Ther Patents 12:489–501

    Article  CAS  Google Scholar 

  76. Baraldi PG, Cacciari B, Spalluto G et al (1996) Novel N 6-(substituted-phenylcarbamoyl)adenosine-5′-uronamides as potent agonists for A3 adenosine receptors. J Med Chem 39:802–806

    Article  PubMed  CAS  Google Scholar 

  77. Baraldi PG, Cacciari B, de Las Infantas MJP et al (1998) Synthesis and biological activity of a new series of N 6-arylcarbamoyl, 2-(ar)alkynyl-N 6-arylcarbamoyl, and N 6-carboxamido derivatives of adenosine-5′-N-ethyluronamide as A1 and A3 adenosine receptor agonists. J Med Chem 41:3174–3185

    Article  PubMed  CAS  Google Scholar 

  78. Baraldi PG, Fruttarolo F, Tabrizi MA et al (2004) Synthesis and biological evaluation of novel N 6-[4-(substituted)sulfonamidophenylcarbamoyl]adenosine-5′-uronamides as A3 adenosine receptor agonists. J Med Chem 47:5535–5540

    Article  PubMed  CAS  Google Scholar 

  79. Baraldi PG, Preti D, Tabrizi MA et al (2007) Synthesis and biological evaluation of novel 1-deoxy-1-[6-[((hetero)arylcarbonyl)hydrazino]- 9H-purin-9-yl]-N-ethyl-b-D-ribofuranuronamide derivatives as useful templates for the development of A2B adenosine receptor agonists. J Med Chem 50:374–380

    Article  PubMed  CAS  Google Scholar 

  80. Baraldi PG, Borea PA, Moorman AR, Preti D (2007) Adenosine A2B receptor agonists. US Patent 2007281902

  81. Lambertucci C, Volpini R, Costanzi S et al (2003) 2-Phenylhydroxypropynyladenosine derivatives as high potent agonists at A2B adenosine receptor subtype. Nucleos Nucleot Nucl 22:809–812

    Article  CAS  Google Scholar 

  82. Volpini R, Costanzi S, Lambertucci C et al (2002) N 6-Alkyl-2-alkynyl derivatives of adenosine as potent and selective agonists at the human adenosine A3 receptor and a starting point for searching A2B ligands. J Med Chem 45:3271–3279

    Article  PubMed  CAS  Google Scholar 

  83. Klotz K-N, Camaioni E, Volpini R et al (1999) 2-Substituted N-ethylcarboxamidoadenosine derivatives as high-affinity agonists at the human A3 adenosine receptors. Naunyn Schmiedebergs Arch Pharmacol 360:103–108

    Article  PubMed  CAS  Google Scholar 

  84. Ivanov AA, Palyulin VA, Zefirov NS (2007) Computer aided comparative analysis of the binding modes of the adenosine receptor agonists for all known subtypes of adenosine receptors. J Mol Graph Model 25:740–754

    Article  PubMed  CAS  Google Scholar 

  85. Gao ZG, Mamedova L, Chen P et al (2004) 2-Substituted adenosine derivatives: Affinity and efficacy at four subtypes of human adenosine receptors. Biochem Pharmacol 68:1985–1993

    Article  PubMed  CAS  Google Scholar 

  86. Adachi H, Palaniappan KK, Ivanov AA et al (2007) Structure-activity relationships of 2,N 6,5′-substituted adenosine derivatives with potent activity at the A2B adenosine receptor. J Med Chem 50:1810–1827

    Article  PubMed  CAS  Google Scholar 

  87. Rosentreter U, Kraemer T, Shimada M et al (2003) Substituted 2-thio-3,5-dicyano-4-phenyl-6-aminopyridines and their use as adenosine receptor-selective ligands. WO Patent 2003008384

  88. Beukers MW, Chang LCW, von Frijtag Drabbe Kunzel JK et al (2004) New, non-adenosine, high-potency agonists for the human adenosine A2B receptor with an improved selectivity profile compared to the reference agonist N-ethylcarboxamidoadenosine. J Med Chem 47:3707–3709

    Article  PubMed  CAS  Google Scholar 

  89. Nell P, Albrecht-Küpper B, Hübsch W et al (2007) Use of adenosine A1 and/or dual A1/A2B agonists for production of medicaments for treating diseases. WO Patent 2007101531

  90. Ergueden J-K, Karig G, Rosentreter U et al (2006) Substituted phenylaminothiazoles and use thereof. WO Patent 2006027142

  91. Krahn T, Kraemer T, Rosentreter U et al (2006) Use of substituted 2-thio-3,5-dicyano-4-phenyl-6-aminopyridines for the treatment of reperfusion injury and reperfusion damage. WO Patent 2006099958

  92. Albrecht B, Krahn T, Phillip S et al (2006) Selective adenosine A2B receptor activation mimics postconditioning in a rabbit infarct model. Circulation (Abstracts From Scientific Sessions) abstract 217, 114(18, Suppl 2)

  93. Krahn T, Thielemann W, Rosentreter U et al (2006) Use of substituted 2-thio-3,5-dicyano-4-phenyl-6-aminopyridines for the treatment of nausea and vomiting. WO Patent 2006002823

Download references

Author information

Authors and Affiliations

  1. Dipartimento di Scienze Farmaceutiche, Università di Ferrara, Via fossato di Mortara 17-19, 44100, Ferrara, Italy

    Pier Giovanni Baraldi, Mojgan Aghazadeh Tabrizi, Francesca Fruttarolo, Romeo Romagnoli & Delia Preti

Authors
  1. Pier Giovanni Baraldi
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Mojgan Aghazadeh Tabrizi
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Francesca Fruttarolo
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Romeo Romagnoli
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Delia Preti
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Pier Giovanni Baraldi.

Additional information

This article has previously been published in issue 4/4, under doi:10.1007/s11302-008-9097-z.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Baraldi, P.G., Tabrizi, M.A., Fruttarolo, F. et al. Recent improvements in the development of A2B adenosine receptor agonists. Purinergic Signalling 5, 3–19 (2009). https://doi.org/10.1007/s11302-009-9140-8

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11302-009-9140-8

Keywords

Search

Navigation