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Agonists and Antagonists for Purinergic Receptors

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Purinergic Signaling

Part of the book series: Methods in Molecular Biology ((MIMB,volume 2041))

Abstract

Membrane receptors that are activated by the purine nucleoside adenosine (adenosine receptors) or by purine or pyrimidine nucleotides (P2Y and P2X receptors) transduce extracellular signals to the cytosol. They play important roles in physiology and disease. The G protein-coupled adenosine receptors comprise four subtypes: A1, A2A, A2B, and A3. The G-protein-coupled P2Y receptors are subdivided into eight subtypes: P2Y1, P2Y2, P2Y4, P2Y6, P2Y11, P2Y12, P2Y13, and P2Y14, while the P2X receptors represent ATP-gated homomeric or heteromeric ion channels consisting of three subunits; the most important subunits are P2X1, P2X2, P2X3, P2X4, and P2X7. This chapter provides guidance for selecting suitable tool compounds for studying these large and important purine receptor families.

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References

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

    Article  CAS  PubMed  Google Scholar 

  2. Fredholm BB, IJzerman AP, Jacobson KA et al (2011) International Union of Basic and Clinical Pharmacology. LXXXI. Nomenclature and classification of adenosine receptors – an update. Pharmacol Rev 63:1–34

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Abbracchio MP, Burnstock G, Boeynaems JM et al (2006) International Union of Pharmacology. LVIII: Update on the P2Y G protein-coupled nucleotide receptors: from molecular mechanisms and pathophysiology to therapy. Pharmacol Rev 58:281–341

    Article  CAS  PubMed  Google Scholar 

  4. Khakh BS, Burnstock G, Kennedy C et al (2001) International Union of Pharmacology. XXIV. Current status of the nomenclature and properties of P2X receptors and their subunits. Pharmacol Rev 53:107–118

    CAS  PubMed  Google Scholar 

  5. Jacobson KA, Müller CE (2016) Medicinal chemistry of adenosine, P2Y and P2X receptors. Neuropharmacology 104:31–49

    Article  CAS  PubMed  Google Scholar 

  6. Rafehi M, Müller CE (2018) Tools and drugs for uracil nucleotide-activated P2Y receptors. Pharmacol Ther 190:24–80

    Article  CAS  PubMed  Google Scholar 

  7. Habermacher C, Dunning K, Chataigneau T et al (2016) Molecular structure and function of P2X receptors. Neuropharmacology 104:18–30

    Article  CAS  PubMed  Google Scholar 

  8. Thimm D, Knospe M, Abdelrahman A et al (2013) Characterization of new G protein-coupled adenine receptors in mouse and hamster. Purinergic Signal 9:415–426

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Thimm D, Schiedel AC, Peti-Peterdi J et al (2015) The nucleobase adenine as a signalling molecule in the kidney. Acta Physiol 213:808–818

    Article  CAS  Google Scholar 

  10. Burnstock G (2017) Purinergic signalling: therapeutic developments. Front Pharmacol 8:661

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Baqi Y, Müller CE (2018) Antithrombotic P2Y12 receptor antagonists: recent developments in drug discovery. Drug Discov Today. https://doi.org/10.1016/j.drudis.2018.09.021

  12. von Kügelgen I (2017) Structure, pharmacology and roles in physiology of the P2Y12 receptor. Adv Exp Med Biol 1051:123–138

    Article  Google Scholar 

  13. Abdulqawi R, Dockry R, Holt K et al (2015) P2X3 receptor antagonist (AF-219) in refractory chronic cough: a randomised, double-blind, placebo-controlled phase 2 study. Lancet 385:1198–1205

    Article  CAS  PubMed  Google Scholar 

  14. Meibom D, Albrecht-Küpper B, Diedrichs N et al (2017) Neladenoson bialanate hydrochloride: a prodrug of a partial adenosine A1 receptor agonist for the chronic treatment of heart diseases. ChemMedChem 12:728–737

    Article  CAS  PubMed  Google Scholar 

  15. Congreve M, Brown GA, Borodovsky A et al (2018) Targeting adenosine A2A receptor antagonism for treatment of cancer. Expert Opin Drug Discov 13:997–1003

    Article  CAS  PubMed  Google Scholar 

  16. Lukashev D, Sitkovsky M, Ohta A (2007) From “Hellstrom Paradox” to anti-adenosinergic cancer immunotherapy. Purinergic Signal 3:129–134

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Vijayan D, Young A, Teng MWL et al (2017) Targeting immunosuppressive adenosine in cancer. Nat Rev Cancer 17:709–724

    Article  CAS  PubMed  Google Scholar 

  18. Hinz S, Navarro G, Borroto-Escuela D et al (2018) Adenosine A2A receptor ligand recognition and signaling is blocked by A2B receptors. Oncotarget 9:13593–13611

    Article  PubMed  PubMed Central  Google Scholar 

  19. Müller CE, Baqi Y, Hinz S et al (2018) Chapter 6: Medicinal chemistry of A2B adenosine receptors. In: Borea PA et al (eds) The adenosine receptors. Springer Nature Switzerland AG, Switzerland, pp 137–168

    Chapter  Google Scholar 

  20. Jazayeri A, Andrews SP, Marshall FH (2017) Structurally enabled discovery of adenosine A2A receptor antagonists. Chem Rev 117:21–37

    Article  CAS  PubMed  Google Scholar 

  21. Glukhova A, Thal DM, Nguyen AT et al (2017) Structure of the adenosine A1 receptor reveals the basis for subtype selectivity. Cell 168:867–877.e13

    Article  CAS  PubMed  Google Scholar 

  22. Franchetti P, Cappellacci L, Vita P et al (2009) N6-cycloalkyl- and N6-bicycloalkyl-C5′(C2′)-modified adenosine derivatives as high-affinity and selective agonists at the human A1 adenosine receptor with antinociceptive effects in mice. J Med Chem 52:2393–2406

    Article  CAS  PubMed  Google Scholar 

  23. Alnouri MW, Jepards S, Casari A et al (2015) Selectivity is species-dependent: characterization of standard agonists and antagonists at human, rat, and mouse adenosine receptors. Purinergic Signal 11:389–407

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Müller CE, Jacobson KA (2011) Recent developments in adenosine receptor ligands and their potential as novel drugs. Biochim Biophys Acta 1808:1290–1308

    Article  CAS  PubMed  Google Scholar 

  25. El-Tayeb A, Michael S, Abdelrahman A et al (2011) Development of polar adenosine A2A receptor agonists for inflammatory bowel disease: synergism with A2B antagonists. ACS Med Chem Lett 2:890–895

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Hinz S, Lacher SK, Seibt BF et al (2014) BAY60-6583 acts as a partial agonist at adenosine A2B receptors. J Pharmacol Exp Ther 349:427–436

    Article  CAS  PubMed  Google Scholar 

  27. Müller CE, Jacobson KA (2011) Xanthines as adenosine receptor antagonists. Handb Exp Pharmacol 200:151–199

    Article  CAS  Google Scholar 

  28. Weyler S, Fülle F, Diekmann M et al (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 1:891–902

    Article  CAS  PubMed  Google Scholar 

  29. Kalk P, Eggert B, Relle K et al (2007) The adenosine A1 receptor antagonist SLV320 reduces myocardial fibrosis in rats with 5/6 nephrectomy without affecting blood pressure. Br J Pharmacol 151:1025–1032

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Takahashi M, Fujita M, Asai N et al (2018) Safety and effectiveness of istradefylline in patients with Parkinson’s disease: interim analysis of a post-marketing surveillance study in Japan. Expert Opin Pharmacother 19:1635–1642

    Article  CAS  PubMed  Google Scholar 

  31. 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 69:3308–3318

    Article  CAS  PubMed  Google Scholar 

  32. Sauer R, Maurinsh J, Reith U et al (2000) Water-soluble phosphate prodrugs of 1-propargyl-8-styrylxanthine derivatives, A2A-selective adenosine receptor antagonists. J Med Chem 43:440–448

    Article  CAS  PubMed  Google Scholar 

  33. Faivre E, Coelho JE, Zornbach K et al (2018) Beneficial effect of a selective adenosine A2A receptor antagonist in the APPswe/PS1dE9 mouse model of Alzheimer’s disease. Front Mol Neurosci 11:235

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Stocchi F, Rascol O, Hauser RA et al (2017) Randomized trial of preladenant, given as monotherapy, in patients with early Parkinson disease. Neurology 88:2198–2206

    Article  CAS  PubMed  Google Scholar 

  35. Kim YC, 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  CAS  PubMed  Google Scholar 

  36. Borrmann T, Hinz S, Bertarelli DC et al (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 52:3994–4006

    Article  CAS  PubMed  Google Scholar 

  37. Hayallah AM, Sandoval-Ramirez J, Reith U et al (2002) 1,8-Disubstituted xanthine derivatives: synthesis of potent A2B-selective adenosine receptor antagonists. J Med Chem 45:1500–1510

    Article  CAS  PubMed  Google Scholar 

  38. Cagnina RE, Ramos SI, Marshall MA et al (2009) Adenosine A2B receptors are highly expressed on murine type II alveolar epithelial cells. Am J Physiol Lung Cell Mol Physiol 297:L467–L474

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Müller CE (2003) Medicinal chemistry of adenosine A3 receptor ligands. Curr Top Med Chem 3:445–462

    Article  PubMed  Google Scholar 

  40. Baraldi PG, Preti D, Borea PA et al (2012) Medicinal chemistry of A3 adenosine receptor modulators: pharmacological activities and therapeutic implications. J Med Chem 55:5676–5703

    Article  CAS  PubMed  Google Scholar 

  41. Borea PA, Varani K, Vincenzi F et al (2015) The A3 adenosine receptor: history and perspectives. Pharmacol Rev 67:74–102

    Article  CAS  PubMed  Google Scholar 

  42. Ozola V, Thorand M, Diekmann M et al (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 11:347–356

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Müller CE, Schiedel AC, Baqi Y (2012) Allosteric modulators of rhodopsin-like G protein-coupled receptors: opportunities in drug development. Pharmacol Ther 135:292–315

    Article  CAS  PubMed  Google Scholar 

  44. Wootten D, Christopoulos A, Sexton PM (2013) Emerging paradigms in GPCR allostery: implications for drug discovery. Nat Rev Drug Discov 12:630–644

    Article  CAS  PubMed  Google Scholar 

  45. Gao ZG, Jacobson KA (2013) Allosteric modulation and functional selectivity of G protein-coupled receptors. Drug Discov Today Technol 10:e237–e243

    Article  PubMed  Google Scholar 

  46. Zhang K, Zhang J, Gao ZG et al (2014) Structure of the human P2Y12 receptor in complex with an antithrombotic drug. Nat 509:115–118

    Google Scholar 

  47. Zhang J, Zhang K, Gao ZG et al (2014) Agonist-bound structure of the human P2Y12 receptor. Nat 509:119–122

    Google Scholar 

  48. Zhang D, Gao ZG, Zhang K et al (2015) Two disparate ligand-binding sites in the human P2Y1 receptor. Nature 520:317–321

    Google Scholar 

  49. von Kügelgen I, Hoffmann K (2016) Pharmacology and structure of P2Y receptors. Neuropharmacology 104:50–61

    Article  CAS  Google Scholar 

  50. Meis S, Hamacher A, Hongwiset D et al (2010) NF546 [4,4′-(carbonylbis(imino-3,1-phenylene-carbonylimino-3,1-(4-methyl-phenylene)-carbonylimino))-bis(1,3-xylene-alpha,alpha′-diphosphonic acid)tetrasodium salt] is a non-nucleotide P2Y11 agonist and stimulates release of interleukin-8 from human monocyte-derived dendritic cells. J Pharmacol Exp Ther 332:238–247

    Article  CAS  PubMed  Google Scholar 

  51. Kawate T (2017) P2X receptor activation. Adv Exp Med Biol 1051:55–69

    Article  PubMed  Google Scholar 

  52. Kasuya G, Yamaura T, Ma XB et al (2017) Structural insights into the competitive inhibition of the ATP-gated P2X receptor channel. Nat Commun 8:876

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Di Virgilio F, Schmalzing G, Markwardt F (2018) The elusive P2X7 macropore. Trends Cell Biol 28:392–404

    Article  CAS  PubMed  Google Scholar 

  54. Rech JC, Bhattacharya A, Letavic MA et al (2016) The evolution of P2X7 antagonists with a focus on CNS indications. Bioorg Med Chem Lett 26:3838–3845

    Article  CAS  PubMed  Google Scholar 

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Author information

Authors and Affiliations

  1. PharmaCenter Bonn, Pharmaceutical Institute, Pharmaceutical & Medicinal Chemistry, University of Bonn, Bonn, Germany

    Christa E. Müller & Vigneshwaran Namasivayam

  2. Department of Chemistry, Sultan Qaboos University, Muscat, Oman

    Younis Baqi

Authors
  1. Christa E. Müller
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  2. Younis Baqi
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  3. Vigneshwaran Namasivayam
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Corresponding author

Correspondence to Christa E. Müller .

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Editors and Affiliations

  1. BioMedical Research Institute of Murcia (IMIB), Clinical University Hospital Virgen de la Arrixaca, Murcia, Spain

    Pablo Pelegrín

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Müller, C.E., Baqi, Y., Namasivayam, V. (2020). Agonists and Antagonists for Purinergic Receptors. In: Pelegrín, P. (eds) Purinergic Signaling. Methods in Molecular Biology, vol 2041. Humana, New York, NY. https://doi.org/10.1007/978-1-4939-9717-6_3

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  • DOI: https://doi.org/10.1007/978-1-4939-9717-6_3

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  • Publisher Name: Humana, New York, NY

  • Print ISBN: 978-1-4939-9716-9

  • Online ISBN: 978-1-4939-9717-6

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