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P2Y receptors C
Unless otherwise stated all data on this page refer to the human proteins. Gene information is provided for human (Hs), mouse (Mm) and rat (Rn).
Overview
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P2Y receptors (nomenclature as agreed by the NC-IUPHAR Subcommittee on P2Y Receptors [2-3,41]) are activated by the endogenous ligands ATP, ADP, UTP, UDP, UDP-glucose and adenosine. The eight mammalian P2Y receptors are activated by distinct nucleotides: P2Y1, P2Y11, P2Y12 and P2Y13 are activated by adenosine-nucleotides; P2Y2, P2Y4 can be activated by both adenosine and uridine nucleotides, with some species-specific differences; P2Y6 is mainly activated by UDP; P2Y14 is preferentially activated by sugar-uracil nucleotides. The missing numbers in the receptor nomenclature refer either to non-mammalian orthologs or receptors having some sequence homology to P2Y receptors but for which there is no functional evidence of responsiveness to nucleotides [70]. Based on their G protein coupling P2Y receptors can be divided into two subfamilies: P2Y1, P2Y2, P2Y4, P2Y6 and P2Y11 receptors couple via Gq proteins to stimulate phospholipase C followed by increases in inositol phosphates and mobilization of Ca2+ from intracellular stores. P2Y11 receptors couple in addition to Gs proteins followed by increased adenylate cyclase activity. In contrast, P2Y12, P2Y13, and P2Y14 receptors signal primarily through activation of Gi proteins and inhibition of adenylate cyclase activity or control of ion channel activity [70]. Clinically used drugs acting on these receptors include the dinucleoside polyphosphate diquafosol, agonist of the P2Y2 receptor subtype, approved in Japan and South Korea for the management of dry eye disease [53], and the P2Y12 receptor antagonists prasugrel, ticagrelor and cangrelor, all approved as antiplatelet drugs [14,65].
Receptors
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P2Y1 receptor
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P2Y2 receptor
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P2Y4 receptor
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P2Y6 receptor
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P2Y11 receptor
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P2Y12 receptor
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P2Y13 receptor
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P2Y14 receptor
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Further reading
* Key recommended reading is highlighted with an asterisk
* Abbracchio MP, Burnstock G, Boeynaems JM, Barnard EA, Boyer JL, Kennedy C, Knight GE, Fumagalli M, Gachet C, Jacobson KA 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 (3): 281-341. [PMID:16968944]
Burnstock G. (2007) Purine and pyrimidine receptors. Cell Mol Life Sci, 64 (12): 1471-83. [PMID:17375261]
Burnstock G, Verkhratsky A. (2012) Purinergic signalling and the nervous system. In (Springer) 1-715.
Erlinge D. (2011) P2Y receptors in health and disease. Adv Pharmacol, 61: 417-39. [PMID:21586366]
Jacobson KA. (2013) Structure-based approaches to ligands for G-protein-coupled adenosine and P2Y receptors, from small molecules to nanoconjugates. J Med Chem, 56 (10): 3749-67. [PMID:23597047]
* Jacobson KA, Delicado EG, Gachet C, Kennedy C, von Kügelgen I, Li B, Miras-Portugal MT, Novak I, Schöneberg T, Perez-Sen R et al.. (2020) Update of P2Y receptor pharmacology: IUPHAR Review 27. Br J Pharmacol, 177 (11): 2413-2433. [PMID:32037507]
Jacobson KA, Ivanov AA, de Castro S, Harden TK, Ko H. (2009) Development of selective agonists and antagonists of P2Y receptors. Purinergic Signal, 5 (1): 75-89. [PMID:18600475]
* Jacobson KA, Paoletta S, Katritch V, Wu B, Gao ZG, Zhao Q, Stevens RC, Kiselev E. (2015) Nucleotides Acting at P2Y Receptors: Connecting Structure and Function. Mol Pharmacol, 88 (2): 220-30. [PMID:25837834]
von Kügelgen I, Harden TK. (2011) Molecular pharmacology, physiology, and structure of the P2Y receptors. Adv Pharmacol, 61: 373-415. [PMID:21586365]
* von Kügelgen I, Hoffmann K. (2016) Pharmacology and structure of P2Y receptors. Neuropharmacology, 104: 50-61. [PMID:26519900]
Weisman GA, Woods LT, Erb L, Seye CI. (2012) P2Y receptors in the mammalian nervous system: pharmacology, ligands and therapeutic potential. CNS Neurol Disord Drug Targets, 11 (6): 722-38. [PMID:22963441]
References
1. A-González N, Castrillo A. (2011) Liver X receptors as regulators of macrophage inflammatory and metabolic pathways. Biochim Biophys Acta, 1812 (8): 982-94. [PMID:21193033]
2. Abbracchio MP, Boeynaems JM, Barnard EA, Boyer JL, Kennedy C, Miras-Portugal MT, King BF, Gachet C, Jacobson KA, Weisman GA et al.. (2003) Characterization of the UDP-glucose receptor (re-named here the P2Y14 receptor) adds diversity to the P2Y receptor family. Trends Pharmacol Sci, 24 (2): 52-5. [PMID:12559763]
3. Abbracchio MP, Burnstock G, Boeynaems JM, Barnard EA, Boyer JL, Kennedy C, Knight GE, Fumagalli M, Gachet C, Jacobson KA 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 (3): 281-341. [PMID:16968944]
4. Amisten S, Braun OO, Johansson L, Ridderstråle M, Melander O, Erlinge D. (2008) The P2Y 13 Met-158-Thr polymorphism, which is in linkage disequilibrium with the P2Y 12 locus, is not associated with acute myocardial infarction. PLoS ONE, 3 (1): e1462. [PMID:18213371]
5. Azran S, Förster D, Danino O, Nadel Y, Reiser G, Fischer B. (2013) Highly efficient biocompatible neuroprotectants with dual activity as antioxidants and P2Y receptor agonists. J Med Chem, 56 (12): 4938-52. [PMID:23751098]
6. Bach P, Boström J, Brickmann K, Burgess LE, Clarke D, Groneberg RD, Harvey DM, Laird ER, O'Sullivan M, Zetterberg F. (2013) 5-alkyl-1,3-oxazole derivatives of 6-amino-nicotinic acids as alkyl ester bioisosteres are antagonists of the P2Y12 receptor. Future Med Chem, 5 (17): 2037-56. [PMID:24215345]
7. Balogh J, Wihlborg AK, Isackson H, Joshi BV, Jacobson KA, Arner A, Erlinge D. (2005) Phospholipase C and cAMP-dependent positive inotropic effects of ATP in mouse cardiomyocytes via P2Y11-like receptors. J Mol Cell Cardiol, 39 (2): 223-30. [PMID:15893764]
8. Barrett MO, Sesma JI, Ball CB, Jayasekara PS, Jacobson KA, Lazarowski ER, Harden TK. (2013) A Selective High-Affinity Antagonist of the P2Y14 Receptor Inhibits UDP-Glucose-Stimulated Chemotaxis of Human Neutrophils. Mol Pharmacol, 84 (1): 41-9. [PMID:23592514]
9. Besada P, Shin DH, Costanzi S, Ko H, Mathé C, Gagneron J, Gosselin G, Maddileti S, Harden TK, Jacobson KA. (2006) Structure-activity relationships of uridine 5'-diphosphate analogues at the human P2Y6 receptor. J Med Chem, 49 (18): 5532-43. [PMID:16942026]
10. Bogdanov YD, Wildman SS, Clements MP, King BF, Burnstock G. (1998) Molecular cloning and characterization of rat P2Y4 nucleotide receptor. Br J Pharmacol, 124 (3): 428-30. [PMID:9647463]
11. Boyer JL, Romero-Avila T, Schachter JB, Harden TK. (1996) Identification of competitive antagonists of the P2Y1 receptor. Mol Pharmacol, 50 (5): 1323-9. [PMID:8913364]
12. Brunschweiger A, Müller CE. (2006) P2 receptors activated by uracil nucleotides--an update. Curr Med Chem, 13 (3): 289-312. [PMID:16475938]
13. Büscher R, Hoerning A, Patel HH, Zhang S, Arthur DB, Grasemann H, Ratjen F, Insel PA. (2006) P2Y2 receptor polymorphisms and haplotypes in cystic fibrosis and their impact on Ca2+ influx. Pharmacogenet Genomics, 16 (3): 199-205. [PMID:16495779]
14. Capodanno D, Ferreiro JL, Angiolillo DJ. (2013) Antiplatelet therapy: new pharmacological agents and changing paradigms. J Thromb Haemost, 11 Suppl 1: 316-29. [PMID:23809135]
15. Carter RL, Fricks IP, Barrett MO, Burianek LE, Zhou Y, Ko H, Das A, Jacobson KA, Lazarowski ER, Harden TK. (2009) Quantification of Gi-mediated inhibition of adenylyl cyclase activity reveals that UDP is a potent agonist of the human P2Y14 receptor. Mol Pharmacol, 76 (6): 1341-8. [PMID:19759354]
16. Cattaneo M, Lecchi A, Ohno M, Joshi BV, Besada P, Tchilibon S, Lombardi R, Bischofberger N, Harden TK, Jacobson KA. (2004) Antiaggregatory activity in human platelets of potent antagonists of the P2Y 1 receptor. Biochem Pharmacol, 68 (10): 1995-2002. [PMID:15476670]
17. Cattaneo M, Zighetti ML, Lombardi R, Martinez C, Lecchi A, Conley PB, Ware J, Ruggeri ZM. (2003) Molecular bases of defective signal transduction in the platelet P2Y12 receptor of a patient with congenital bleeding. Proc Natl Acad Sci USA, 100 (4): 1978-83. [PMID:12578987]
18. Cavallari U, Trabetti E, Malerba G, Biscuola M, Girelli D, Olivieri O, Martinelli N, Angiolillo DJ, Corrocher R, Pignatti PF. (2007) Gene sequence variations of the platelet P2Y12 receptor are associated with coronary artery disease. BMC Med Genet, 8: 59. [PMID:17803810]
19. Chambers JK, Macdonald LE, Sarau HM, Ames RS, Freeman K, Foley JJ, Zhu Y, McLaughlin MM, Murdock P, McMillan L et al.. (2000) A G protein-coupled receptor for UDP-glucose. J Biol Chem, 275 (15): 10767-71. [PMID:10753868]
20. Chhatriwala M, Ravi RG, Patel RI, Boyer JL, Jacobson KA, Harden TK. (2004) Induction of novel agonist selectivity for the ADP-activated P2Y1 receptor versus the ADP-activated P2Y12 and P2Y13 receptors by conformational constraint of an ADP analog. J Pharmacol Exp Ther, 311 (3): 1038-43. [PMID:15345752]
21. Communi D, Parmentier M, Boeynaems JM. (1996) Cloning, functional expression and tissue distribution of the human P2Y6 receptor. Biochem Biophys Res Commun, 222 (2): 303-8. [PMID:8670200]
22. Communi D, Robaye B, Boeynaems JM. (1999) Pharmacological characterization of the human P2Y11 receptor. Br J Pharmacol, 128 (6): 1199-206. [PMID:10578132]
23. Das A, Ko H, Burianek LE, Barrett MO, Harden TK, Jacobson KA. (2010) Human P2Y(14) receptor agonists: truncation of the hexose moiety of uridine-5'-diphosphoglucose and its replacement with alkyl and aryl groups. J Med Chem, 53 (1): 471-80. [PMID:19902968]
24. El-Tayeb A, Griessmeier KJ, Müller CE. (2005) Synthesis and preliminary evaluation of [3H]PSB-0413, a selective antagonist radioligand for platelet P2Y12 receptors. Bioorg Med Chem Lett, 15 (24): 5450-2. [PMID:16213725]
25. El-Tayeb A, Qi A, Müller CE. (2006) Synthesis and structure-activity relationships of uracil nucleotide derivatives and analogues as agonists at human P2Y2, P2Y4, and P2Y6 receptors. J Med Chem, 49 (24): 7076-87. [PMID:17125260]
26. El-Tayeb A, Qi A, Nicholas RA, Müller CE. (2011) Structural modifications of UMP, UDP, and UTP leading to subtype-selective agonists for P2Y2, P2Y4, and P2Y6 receptors. J Med Chem, 54 (8): 2878-90. [PMID:21417463]
27. Fricks IP, Carter RL, Lazarowski ER, Harden TK. (2009) Gi-dependent cell signaling responses of the human P2Y14 receptor in model cell systems. J Pharmacol Exp Ther, 330 (1): 162-8. [PMID:19339661]
28. Fricks IP, Maddileti S, Carter RL, Lazarowski ER, Nicholas RA, Jacobson KA, Harden TK. (2008) UDP is a competitive antagonist at the human P2Y14 receptor. J Pharmacol Exp Ther, 325 (2): 588-94. [PMID:18252808]
29. Gao ZG, Mamedova L, Tchilibon S, Gross AS, Jacobson KA. (2004) 2,2'-Pyridylisatogen tosylate antagonizes P2Y1 receptor signaling without affecting nucleotide binding. Biochem Pharmacol, 68 (2): 231-7. [PMID:15193995]
30. Ginsburg-Shmuel T, Haas M, Grbic D, Arguin G, Nadel Y, Gendron FP, Reiser G, Fischer B. (2012) UDP made a highly promising stable, potent, and selective P2Y6-receptor agonist upon introduction of a boranophosphate moiety. Bioorg Med Chem, 20 (18): 5483-95. [PMID:22901672]
31. Haas M, Ginsburg-Shmuel T, Fischer B, Reiser G. (2014) 5-OMe-uridine-5'-O-(α-boranodiphosphate), a novel nucleotide derivative highly active at the human P2Y(6) receptor protects against death-receptor mediated glial apoptosis. Neurosci Lett, 578: 80-4. [PMID:24970757]
32. Hetherington SL, Singh RK, Lodwick D, Thompson JR, Goodall AH, Samani NJ. (2005) Dimorphism in the P2Y1 ADP receptor gene is associated with increased platelet activation response to ADP. Arterioscler Thromb Vasc Biol, 25 (1): 252-7. [PMID:15514209]
33. Hillmann P, Ko GY, Spinrath A, Raulf A, von Kügelgen I, Wolff SC, Nicholas RA, Kostenis E, Höltje HD, Müller CE. (2009) Key determinants of nucleotide-activated G protein-coupled P2Y(2) receptor function revealed by chemical and pharmacological experiments, mutagenesis and homology modeling. J Med Chem, 52 (9): 2762-75. [PMID:19419204]
34. Hollopeter G, Jantzen HM, Vincent D, Li G, England L, Ramakrishnan V, Yang RB, Nurden P, Nurden A, Julius D et al.. (2001) Identification of the platelet ADP receptor targeted by antithrombotic drugs. Nature, 409 (6817): 202-7. [PMID:11196645]
35. Humphries RG, Tomlinson W, Clegg JA, Ingall AH, Kindon ND, Leff P. (1995) Pharmacological profile of the novel P2T-purinoceptor antagonist, FPL 67085 in vitro and in the anaesthetized rat in vivo. Br J Pharmacol, 115 (6): 1110-6. [PMID:7582510]
36. Humphries RG, Tomlinson W, Ingall AH, Cage PA, Leff P. (1994) FPL 66096: a novel, highly potent and selective antagonist at human platelet P2T-purinoceptors. Br J Pharmacol, 113 (3): 1057-63. [PMID:7858849]
37. Ito M, Egashira SI, Yoshida K, Mineno T, Kumagai K, Kojima H, Okabe T, Nagano T, Ui M, Matsuoka I. (2017) Identification of novel selective P2Y6 receptor antagonists by high-throughput screening assay. Life Sci, 180: 137-142. [PMID:28527783]
38. Ivanov AA, Fricks I, Kendall Harden T, Jacobson KA. (2007) Molecular dynamics simulation of the P2Y14 receptor. Ligand docking and identification of a putative binding site of the distal hexose moiety. Bioorg Med Chem Lett, 17: 761-766. [PMID:17088057]
39. Ivanov AA, Ko H, Cosyn L, Maddileti S, Besada P, Fricks I, Costanzi S, Harden TK, Calenbergh SV, Jacobson KA. (2007) Molecular modeling of the human P2Y2 receptor and design of a selective agonist, 2'-amino-2'-deoxy-2-thiouridine 5'-triphosphate. J Med Chem, 50 (6): 1166-76. [PMID:17302398]
40. Jacobson KA, Deflorian F, Mishra S, Costanzi S. (2011) Pharmacochemistry of the platelet purinergic receptors. Purinergic Signal, 7 (3): 305-24. [PMID:21484092]
41. Jacobson KA, Delicado EG, Gachet C, Kennedy C, von Kügelgen I, Li B, Miras-Portugal MT, Novak I, Schöneberg T, Perez-Sen R et al.. (2020) Update of P2Y receptor pharmacology: IUPHAR Review 27. Br J Pharmacol, 177 (11): 2413-2433. [PMID:32037507]
42. Jacobson KA, Ivanov AA, de Castro S, Harden TK, Ko H. (2009) Development of selective agonists and antagonists of P2Y receptors. Purinergic Signal, 5 (1): 75-89. [PMID:18600475]
43. Jacobson KA, Jarvis MF, Williams M. (2002) Purine and pyrimidine (P2) receptors as drug targets. J Med Chem, 45 (19): 4057-93. [PMID:12213051]
44. Janssens R, Paindavoine P, Parmentier M, Boeynaems JM. (1999) Human P2Y2 receptor polymorphism: identification and pharmacological characterization of two allelic variants. Br J Pharmacol, 127 (3): 709-16. [PMID:10401562]
45. Jayasekara PS, Barrett MO, Ball CB, Brown KA, Hammes E, Balasubramanian R, Harden TK, Jacobson KA. (2014) 4-Alkyloxyimino derivatives of uridine-5'-triphosphate: distal modification of potent agonists as a strategy for molecular probes of P2Y2, P2Y4, and P2Y6 receptors. J Med Chem, 57 (9): 3874-83. [PMID:24712832]
46. Kemp PA, Sugar RA, Jackson AD. (2004) Nucleotide-mediated mucin secretion from differentiated human bronchial epithelial cells. Am J Respir Cell Mol Biol, 31 (4): 446-55. [PMID:15231488]
47. Kennedy C, Qi AD, Herold CL, Harden TK, Nicholas RA. (2000) ATP, an agonist at the rat P2Y(4) receptor, is an antagonist at the human P2Y(4) receptor. Mol Pharmacol, 57 (5): 926-31. [PMID:10779375]
48. Kim HS, Ohno M, Xu B, Kim HO, Choi Y, Ji XD, Maddileti S, Marquez VE, Harden TK, Jacobson KA. (2003) 2-Substitution of adenine nucleotide analogues containing a bicyclo[3.1.0]hexane ring system locked in a northern conformation: enhanced potency as P2Y1 receptor antagonists. J Med Chem, 46 (23): 4974-87. [PMID:14584948]
49. Kim HS, Ravi RG, Marquez VE, Maddileti S, Wihlborg AK, Erlinge D, Malmsjö M, Boyer JL, Harden TK, Jacobson KA. (2002) Methanocarba modification of uracil and adenine nucleotides: high potency of Northern ring conformation at P2Y1, P2Y2, P2Y4, and P2Y11 but not P2Y6 receptors. J Med Chem, 45 (1): 208-18. [PMID:11754592]
50. Kim YC, Lee JS, Sak K, Marteau F, Mamedova L, Boeynaems JM, Jacobson KA. (2005) Synthesis of pyridoxal phosphate derivatives with antagonist activity at the P2Y13 receptor. Biochem Pharmacol, 70 (2): 266-74. [PMID:15913566]
51. Kiselev E, Balasubramanian R, Uliassi E, Brown KA, Trujillo K, Katritch V, Hammes E, Stevens RC, Harden TK, Jacobson KA. (2015) Design, synthesis, pharmacological characterization of a fluorescent agonist of the P2Y₁₄ receptor. Bioorg Med Chem Lett, 25 (21): 4733-9. [PMID:26303895]
52. Kiselev E, Barrett MO, Katritch V, Paoletta S, Weitzer CD, Brown KA, Hammes E, Yin AL, Zhao Q, Stevens RC et al.. (2014) Exploring a 2-naphthoic acid template for the structure-based design of P2Y14 receptor antagonist molecular probes. ACS Chem Biol, 9 (12): 2833-42. [PMID:25299434]
53. Lau OC, Samarawickrama C, Skalicky SE. (2014) P2Y2 receptor agonists for the treatment of dry eye disease: a review. Clin Ophthalmol, 8: 327-34. [PMID:24511227]
54. Lazarowski ER, Watt WC, Stutts MJ, Boucher RC, Harden TK. (1995) Pharmacological selectivity of the cloned human P2U-purinoceptor: potent activation by diadenosine tetraphosphate. Br J Pharmacol, 116 (1): 1619-27. [PMID:8564228]
55. Lazarowski ER, Watt WC, Stutts MJ, Brown HA, Boucher RC, Harden TK. (1996) Enzymatic synthesis of UTP gamma S, a potent hydrolysis resistant agonist of P2U-purinoceptors. Br J Pharmacol, 117 (1): 203-9. [PMID:8825364]
56. Mamedova LK, Joshi BV, Gao ZG, von Kügelgen I, Jacobson KA. (2004) Diisothiocyanate derivatives as potent, insurmountable antagonists of P2Y6 nucleotide receptors. Biochem Pharmacol, 67 (9): 1763-70. [PMID:15081875]
57. Marteau F, Le Poul E, Communi D, Communi D, Labouret C, Savi P, Boeynaems JM, Gonzalez NS. (2003) Pharmacological characterization of the human P2Y13 receptor. Mol Pharmacol, 64 (1): 104-12. [PMID:12815166]
58. Maruoka H, Barrett MO, Ko H, Tosh DK, Melman A, Burianek LE, Balasubramanian R, Berk B, Costanzi S, Harden TK et al.. (2010) Pyrimidine ribonucleotides with enhanced selectivity as P2Y(6) receptor agonists: novel 4-alkyloxyimino, (S)-methanocarba, and 5'-triphosphate gamma-ester modifications. J Med Chem, 53 (11): 4488-501. [PMID:20446735]
59. Maruoka H, Jayasekara MP, Barrett MO, Franklin DA, de Castro S, Kim N, Costanzi S, Harden TK, Jacobson KA. (2011) Pyrimidine nucleotides with 4-alkyloxyimino and terminal tetraphosphate δ-ester modifications as selective agonists of the P2Y(4) receptor. J Med Chem, 54 (12): 4018-33. [PMID:21528910]
60. Meis S, Hamacher A, Hongwiset D, Marzian C, Wiese M, Eckstein N, Royer HD, Communi D, Boeynaems JM, Hausmann R 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 (1): 238-47. [PMID:19815812]
61. Morrow GB, Nicholas RA, Kennedy C. (2014) UTP is not a biased agonist at human P2Y(11) receptors. Purinergic Signal, 10 (4): 581-5. [PMID:25015314]
62. Mufti F, Jung YH, Giancotti LA, Yu J, Chen Z, Phung NB, Jacobson KA, Salvemini D. (2020) P2Y14 Receptor Antagonists Reverse Chronic Neuropathic Pain in a Mouse Model. ACS Med Chem Lett, 11 (6): 1281-1286. [PMID:32551012]
63. Ohlmann P, Lecchi A, El-Tayeb A, Müller CE, Cattaneo M, Gachet C. (2013) The platelet P2Y(12) receptor under normal and pathological conditions. Assessment with the radiolabeled selective antagonist [(3)H]PSB-0413. Purinergic Signal, 9 (1): 59-66. [PMID:22892887]
64. Pendergast W, Yerxa BR, Douglass 3rd JG, Shaver SR, Dougherty RW, Redick CC, Sims IF, Rideout JL. (2001) Synthesis and P2Y receptor activity of a series of uridine dinucleoside 5'-polyphosphates. Bioorg Med Chem Lett, 11 (2): 157-60. [PMID:11206448]
65. Price MJ. (2017) Cangrelor: Pharmacology, Clinical Data, and Role in Percutaneous Coronary Intervention. Interv Cardiol Clin, 6 (1): 39-47. [PMID:27886821]
66. Rafehi M, Malik EM, Neumann A, Abdelrahman A, Hanck T, Namasivayam V, Müller CE, Baqi Y. (2017) Development of Potent and Selective Antagonists for the UTP-Activated P2Y4 Receptor. J Med Chem, 60 (7): 3020-3038. [PMID:28306255]
67. Schachter JB, Harden TK. (1997) An examination of deoxyadenosine 5'(alpha-thio)triphosphate as a ligand to define P2Y receptors and its selectivity as a low potency partial agonist of the P2Y1 receptor. Br J Pharmacol, 121 (2): 338-44. [PMID:9154346]
68. Takasaki J, Kamohara M, Saito T, Matsumoto M, Matsumoto S, Ohishi T, Soga T, Matsushime H, Furuichi K. (2001) Molecular cloning of the platelet P2T(AC) ADP receptor: pharmacological comparison with another ADP receptor, the P2Y(1) receptor. Mol Pharmacol, 60: 432-439. [PMID:11502873]
69. Ullmann H, Meis S, Hongwiset D, Marzian C, Wiese M, Nickel P, Communi D, Boeynaems JM, Wolf C, Hausmann R et al.. (2005) Synthesis and structure-activity relationships of suramin-derived P2Y11 receptor antagonists with nanomolar potency. J Med Chem, 48 (22): 7040-8. [PMID:16250663]
70. von Kügelgen I, Hoffmann K. (2016) Pharmacology and structure of P2Y receptors. Neuropharmacology, 104: 50-61. [PMID:26519900]
71. Waldo GL, Corbitt J, Boyer JL, Ravi G, Kim HS, Ji XD, Lacy J, Jacobson KA, Harden TK. (2002) Quantitation of the P2Y(1) receptor with a high affinity radiolabeled antagonist. Mol Pharmacol, 62 (5): 1249-57. [PMID:12391289]
72. White PJ, Webb TE, Boarder MR. (2003) Characterization of a Ca2+ response to both UTP and ATP at human P2Y11 receptors: evidence for agonist-specific signaling. Mol Pharmacol, 63 (6): 1356-63. [PMID:12761346]
73. Yerxa BR, Sabater JR, Davis CW, Stutts MJ, Lang-Furr M, Picher M, Jones AC, Cowlen M, Dougherty R, Boyer J et al.. (2002) Pharmacology of INS37217 [P(1)-(uridine 5')-P(4)- (2'-deoxycytidine 5')tetraphosphate, tetrasodium salt], a next-generation P2Y(2) receptor agonist for the treatment of cystic fibrosis. J Pharmacol Exp Ther, 302 (3): 871-80. [PMID:12183642]
74. Zech G, Hessler G, Evers A, Weiss T, Florian P, Just M, Czech J, Czechtizky W, Görlitzer J, Ruf S et al.. (2012) Identification of high-affinity P2Y₁₂ antagonists based on a phenylpyrazole glutamic acid piperazine backbone. J Med Chem, 55 (20): 8615-29. [PMID:22984835]
75. Zhang D, Gao ZG, Zhang K, Kiselev E, Crane S, Wang J, Paoletta S, Yi C, Ma L, Zhang W et al.. (2015) Two disparate ligand-binding sites in the human P2Y1 receptor. Nature, 520 (7547): 317-21. [PMID:25822790]
76. Zhang K, Zhang J, Gao ZG, Zhang D, Zhu L, Han GW, Moss SM, Paoletta S, Kiselev E, Lu W et al.. (2014) Structure of the human P2Y12 receptor in complex with an antithrombotic drug. Nature, 509 (7498): 115-8. [PMID:24670650]
NC-IUPHAR subcommittee and family contributors
Subcommittee members:
Maria-Pia Abbracchio (Chairperson)
Kenneth A. Jacobson (Co-chairperson)
Geoffrey Burnstock (Past chairperson)
Jean-Marie Boeynaems
Stefania Ceruti
Marta Fumagalli
Christian Gachet
Brian F. King
Davide Lecca
Christa E. Müller
Gary A. Weisman |
Other contributors:
José L. Boyer
Rebecca Hills
Robert G. Humphries
Kazu Inoue
Maria Teresa Miras-Portugal
Vera Ralevic |
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Concise Guide to PHARMACOLOGY citation:
Alexander SPH, Christopoulos A, Davenport AP, Kelly E, Mathie AA, Peters JA, Veale EL, Armstrong JF, Faccenda E, Harding SD, Davies JA et al. (2023) The Concise Guide to PHARMACOLOGY 2023/24: G protein-coupled receptors. Br J Pharmacol. 180 Suppl 2:S23-S144.
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A series of 4-alkyloxyimino derivatives of uridine-5'-triphosphate which could be useful for derivatization as fluorescent P2Y2/4/6 receptor probes has been synthesized [45].
Single nucleotide polymorphisms of the P2YR1 gene have been associated to different platelet reactivity to ADP [32]. Three frequent nonsynonymous P2Y2 receptor polymorphisms have been identified, one of which was significantly more common in cystic fibrosis patients. This polymorphism is linked to increases in Ca2+ influx in transfected cells, and might therefore play a role in disease development [13]. ATP acts as partial agonist/antagonist at the human P2Y4 receptor [70]. Although UTP was also shown to be a biased agonist at P2Y11, this is still under debate [61,72]. Clinically used drugs acting on these receptors include the dinucleoside polyphosphate diquafosol, agonist of the P2Y2 receptor subtype that is approved in Japan and South Korea for the management of dry eye disease [53], and the P2Y12 receptor antagonists prasugrel, ticagrelor and cangrelor, all approved as antiplatelet drugs [14, 65]. A group of single nucleotide polymorphisms in the P2Y12 gene, forming the so called P2Y12 H2 haplotype, has been associated with increased platelet responsiveness to ADP, increased risk of peripheral arterial disease and with coronary artery disease [18]. The platelet-type bleeding disorder due to P2Y12 receptor defects is an autosomal recessive condition characterized by mild to moderate mucocutaneous bleeding and excessive bleeding after surgery or trauma. The defect is due to the inability of ADP to induce platelet aggregation [17]. The P2Y13 receptor Met-158-Thr polymorphism, which is in linkage disequilibrium with the P2Y12 locus, is not associated with acute myocardial infarction, diabetes mellitus or related risk factors [4]. The P2Y14 receptor, previously considered to exclusively bind sugar nucleotides such as UDP-glucose, UDP-galactose, UDP-glucuronic acid and UDP-N-acethyl-glucosamine [19], has been demonstrated to bind also UDP [15]. UDP was also shown to competitively antagonise the UDP-glucose response at the human recombinant P2Y14 receptor [28].