Display options
Cite
Jacobson KA, Deflorian F, Mishra S, et al. Pharmacochemistry of the platelet purinergic receptors. Purinergic Signal. 2011;7(3):305-24doi: 10.1007/s11302-011-9216-0.
Jacobson, K. A., Deflorian, F., Mishra, S., & Costanzi, S. (2011). Pharmacochemistry of the platelet purinergic receptors. Purinergic signalling, 7(3), 305-24. https://doi.org/10.1007/s11302-011-9216-0
Jacobson, Kenneth A, et al. "Pharmacochemistry of the platelet purinergic receptors." Purinergic signalling vol. 7,3 (2011): 305-24. doi: https://doi.org/10.1007/s11302-011-9216-0
Jacobson KA, Deflorian F, Mishra S, Costanzi S. Pharmacochemistry of the platelet purinergic receptors. Purinergic Signal. 2011 Sep;7(3):305-24. doi: 10.1007/s11302-011-9216-0. Epub 2011 Feb 18. PMID: 21484092; PMCID: PMC3166987.
Copy Download .nbib Format: NLM
Share it on

Purinergic Signal. 2011 Sep;7(3):305-24. doi: 10.1007/s11302-011-9216-0. Epub 2011 Feb 18.

Pharmacochemistry of the platelet purinergic receptors.

Purinergic signalling

Kenneth A Jacobson, Francesca Deflorian, Shilpi Mishra, Stefano Costanzi

Affiliations

  1. Molecular Recognition Section, Laboratory of Bioorganic Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bldg. 8A, Rm. B1A-19, NIH, NIDDK, LBC, Bethesda, MD, 20892-0810, USA, [email protected].

PMID: 21484092 PMCID: PMC3166987 DOI: 10.1007/s11302-011-9216-0

Abstract

Platelets contain at least five purinergic G protein-coupled receptors, e.g., the pro-aggregatory P2Y(1) and P2Y(12) receptors, a P2Y(14) receptor (GPR105) of unknown function, and anti-aggregatory A(2A) and A(2B) adenosine receptor (ARs), in addition to the ligand-gated P2X1 ion channel. Probing the structure-activity relationships (SARs) of the P2X and P2Y receptors for extracellular nucleotides has resulted in numerous new agonist and antagonist ligands. Selective agents derived from known ligands and novel chemotypes can be used to help define the subtypes pharmacologically. Some of these agents have entered into clinical trials in spite of the challenges of drug development for these classes of receptors. The functional architecture of P2 receptors was extensively explored using mutagenesis and molecular modeling, which are useful tools in drug discovery. In general, novel drug delivery methods, prodrug approaches, allosteric modulation, and biased agonism would be desirable to overcome side effects that tend to occur even with receptor subtype-selective ligands. Detailed SAR analyses have been constructed for nucleotide and non-nucleotide ligands at the P2Y(1), P2Y(12), and P2Y(14) receptors. The thienopyridine antithrombotic drugs Clopidogrel and Prasugrel require enzymatic pre-activation in vivo and react irreversibly with the P2Y(12) receptor. There is much pharmaceutical development activity aimed at identifying reversible P2Y(12) receptor antagonists. The screening of chemically diverse compound libraries has identified novel chemotypes that act as competitive, non-nucleotide antagonists of the P2Y(1) receptor or the P2Y(12) receptor, and antithrombotic properties of the structurally optimized analogues were demonstrated. In silico screening at the A(2A) AR has identified antagonist molecules having novel chemotypes. Fluorescent and other reporter groups incorporated into ligands can enable new technology for receptor assays and imaging. The A(2A) agonist CGS21680 and the P2Y(1) receptor antagonist MRS2500 were derivatized for covalent attachment to polyamidoamine dendrimeric carriers of MW 20,000, and the resulting multivalent conjugates inhibited ADP-promoted platelet aggregation. In conclusion, a wide range of new pharmacological tools is available to control platelet function by interacting with cell surface purine receptors.

References

  1. Purinergic Signal. 2005 Jun;1(2):183-91 - PubMed
  2. J Med Chem. 1999 May 6;42(9):1625-38 - PubMed
  3. Eur J Pharmacol. 1999 Feb 12;367(1):119-23 - PubMed
  4. Bioorg Med Chem Lett. 2005 Jul 1;15(13):3292-5 - PubMed
  5. Bioconjug Chem. 2009 Oct 21;20(10):1888-98 - PubMed
  6. Purinergic Signal. 2010 Dec;6(4):383-91 - PubMed
  7. Expert Opin Ther Pat. 2010 May;20(5):625-46 - PubMed
  8. J Med Chem. 2010 Mar 11;53(5):2076-86 - PubMed
  9. Thromb Res. 2010 Feb;125(2):159-65 - PubMed
  10. J Med Chem. 2008 Feb 28;51(4):1007-25 - PubMed
  11. J Biol Chem. 1995 Jun 9;270(23):13987-97 - PubMed
  12. J Biol Chem. 2010 Jul 2;285(27):20644-53 - PubMed
  13. J Med Chem. 2007 Jul 12;50(14):3229-41 - PubMed
  14. Cell Calcium. 2009 Oct;46(4):263-72 - PubMed
  15. J Comput Aided Mol Des. 2006 Jul-Aug;20(7-8):417-26 - PubMed
  16. J Med Chem. 1998 Jun 18;41(13):2201-6 - PubMed
  17. Bioorg Med Chem Lett. 2008 Jun 1;18(11):3338-43 - PubMed
  18. Br J Pharmacol. 2007 Sep;152(1):141-50 - PubMed
  19. Eur J Med Chem. 2009 Apr;44(4):1525-36 - PubMed
  20. Handb Exp Pharmacol. 2009;(193):59-98 - PubMed
  21. Biochem J. 1993 May 1;291 ( Pt 3):875-81 - PubMed
  22. Eur Biophys J. 2009 Mar;38(3):329-38 - PubMed
  23. J Biol Chem. 1998 Jan 23;273(4):2030-4 - PubMed
  24. Bioorg Med Chem Lett. 2010 Feb 15;20(4):1388-94 - PubMed
  25. Biochem Pharmacol. 2008 Mar 15;75(6):1341-7 - PubMed
  26. Naunyn Schmiedebergs Arch Pharmacol. 2005 Jul;372(1):1-13 - PubMed
  27. J Med Chem. 2004 Oct 21;47(22):5393-404 - PubMed
  28. J Med Chem. 2003 Nov 6;46(23):4974-87 - PubMed
  29. J Med Chem. 2002 May 9;45(10):2090-100 - PubMed
  30. Mol Cell Endocrinol. 2011 Feb 10;333(1):8-19 - PubMed
  31. Bioorg Med Chem Lett. 2009 Aug 15;19(16):4657-63 - PubMed
  32. Drug Des Discov. 1995 Nov;13(2):133-54 - PubMed
  33. J Neurosci. 2006 Sep 6;26(36):9340-8 - PubMed
  34. Curr Opin Investig Drugs. 2010 Mar;11(3):340-8 - PubMed
  35. Mol Pharmacol. 1996 Apr;49(4):683-91 - PubMed
  36. J Neurochem. 2005 Feb;92(4):925-33 - PubMed
  37. J Med Chem. 2001 Feb 1;44(3):340-9 - PubMed
  38. J Org Chem. 2002 Nov 15;67(23):8063-71 - PubMed
  39. Br J Pharmacol. 2001 Jan;132(1):47-54 - PubMed
  40. Biochem Pharmacol. 2004 Jul 15;68(2):231-7 - PubMed
  41. Am J Physiol Cell Physiol. 2005 Mar;288(3):C559-67 - PubMed
  42. Br J Clin Pharmacol. 2007 Apr;63(4):421-30 - PubMed
  43. Adv Pharmacol. 2011;61:301-32 - PubMed
  44. Pharmacol Rev. 2006 Sep;58(3):281-341 - PubMed
  45. EMBO J. 2006 Oct 4;25(19):4615-27 - PubMed
  46. J Pharmacol Exp Ther. 2009 Nov;331(2):648-55 - PubMed
  47. Thromb Haemost. 2008 Aug;100(2):261-70 - PubMed
  48. Chem Rev. 2008 Jan;108(1):238-63 - PubMed
  49. Eur J Pharmacol. 2001 Nov 2;430(2-3):203-10 - PubMed
  50. J Med Chem. 2010 May 13;53(9):3748-55 - PubMed
  51. Curr Pharm Des. 2002;8(26):2371-99 - PubMed
  52. Blood. 2003 May 15;101(10):3908-14 - PubMed
  53. Drug Dev Res. 2000 Sep 1;51(1):7-19 - PubMed
  54. J Pharmacol Exp Ther. 2006 Feb;316(2):556-63 - PubMed
  55. Br J Pharmacol. 1996 May;118(1):167-73 - PubMed
  56. Circulation. 2010 Jan 5;121(1):171-9 - PubMed
  57. J Med Chem. 2002 Nov 21;45(24):5384-96 - PubMed
  58. Thromb Haemost. 2010 Oct;104(4):845-57 - PubMed
  59. J Biol Chem. 1999 May 21;274(21):14639-47 - PubMed
  60. Science. 2008 Nov 21;322(5905):1211-7 - PubMed
  61. Bioorg Med Chem Lett. 2011 Jul 15;21(14):4366-8 - PubMed
  62. J Biol Chem. 2008 Apr 18;283(16):11050-63 - PubMed
  63. FEBS Lett. 2003 Feb 11;536(1-3):145-50 - PubMed
  64. Mol Pharmacol. 2003 Nov;64(5):1210-6 - PubMed
  65. Bioorg Med Chem. 2004 Apr 1;12(7):1769-79 - PubMed
  66. Bioorg Med Chem Lett. 2007 Nov 1;17(21):6013-8 - PubMed
  67. Neuropharmacology. 2000 Aug 23;39(11):2044-53 - PubMed
  68. J Med Chem. 2010 Jan 14;53(1):471-80 - PubMed
  69. Eur J Pharmacol. 2001 Feb 2;412(3):213-21 - PubMed
  70. J Thromb Haemost. 2009 Sep;7(9):1556-65 - PubMed
  71. Eur J Pharmacol. 2010 Oct 10;644(1-3):10-6 - PubMed
  72. Br J Pharmacol. 1994 Oct;113(2):614-20 - PubMed
  73. J Neurochem. 2009 May;109(4):1042-52 - PubMed
  74. J Thromb Haemost. 2010 Apr;8(4):817-27 - PubMed
  75. Thromb Res. 2008;122(4):523-32 - PubMed
  76. Mol Pharmacol. 1998 Jun;53(6):969-73 - PubMed
  77. Thromb Res. 2009 Nov;124(5):565-71 - PubMed
  78. Pharmacol Res. 2010 Oct;62(4):344-51 - PubMed
  79. J Med Chem. 2009 Jun 25;52(12):3784-93 - PubMed
  80. J Pharmacol Exp Ther. 2002 Feb;300(2):673-80 - PubMed
  81. Br J Pharmacol. 2006 Mar;147(5):459-67 - PubMed
  82. Eur J Pharmacol. 1999 Jul 2;376(1-2):127-38 - PubMed
  83. J Thromb Haemost. 2008 Aug;6(8):1393-404 - PubMed
  84. J Thromb Haemost. 2008 Nov;6(11):1908-14 - PubMed
  85. Br J Pharmacol. 1999 Nov;128(5):981-8 - PubMed
  86. Drug Dev Res. 2004 Apr;61(4):227-232 - PubMed
  87. Mol Pharmacol. 2006 Jan;69(1):338-45 - PubMed
  88. J Thromb Haemost. 2006 Apr;4(4):861-8 - PubMed
  89. Biochem J. 2008 Jan 1;409(1):107-16 - PubMed
  90. J Med Chem. 1993 Nov 26;36(24):3937-46 - PubMed
  91. Bioorg Med Chem Lett. 2008 Dec 1;18(23):6222-6 - PubMed
  92. Neuropharmacology. 2005 Mar;48(3):461-8 - PubMed
  93. Cell Mol Biol (Noisy-le-grand). 1994 May;40(3):437-42 - PubMed
  94. Pharmacol Rev. 2011 Sep;63(3):641-83 - PubMed
  95. Proc Natl Acad Sci U S A. 2007 Oct 9;104(41):16359-64 - PubMed
  96. Platelets. 2007 Aug;18(5):346-56 - PubMed
  97. J Mol Biol. 2004 Sep 3;342(1):333-43 - PubMed
  98. Mol Pharmacol. 1996 Nov;50(5):1323-9 - PubMed
  99. Bioorg Med Chem Lett. 2001 Jul 23;11(14):1805-8 - PubMed
  100. J Med Chem. 1998 Apr 23;41(9):1456-66 - PubMed
  101. Bioorg Med Chem Lett. 2005 Dec 15;15(24):5450-2 - PubMed
  102. Br J Pharmacol. 1996 Aug;118(8):1959-64 - PubMed
  103. ChemMedChem. 2008 May;3(5):732-6 - PubMed
  104. J Med Chem. 1999 Jan 28;42(2):213-20 - PubMed
  105. Mol Pharmacol. 2009 Dec;76(6):1341-8 - PubMed
  106. J Clin Invest. 1999 Dec;104(12):1731-7 - PubMed
  107. Thromb Haemost. 2005 Sep;94(3):593-8 - PubMed
  108. J Med Chem. 2005 Apr 21;48(8):2763-6 - PubMed
  109. Bioconjug Chem. 2010 Jul 21;21(7):1190-205 - PubMed
  110. Mol Pharmacol. 2002 Nov;62(5):1249-57 - PubMed
  111. J Pharmacol Exp Ther. 2004 Dec;311(3):1038-43 - PubMed
  112. J Med Chem. 2002 Jan 3;45(1):208-18 - PubMed
  113. Br J Pharmacol. 1995 Nov;116(6):2611-6 - PubMed
  114. Thromb Haemost. 2000 Nov;84(5):891-6 - PubMed
  115. J Med Chem. 2002 Sep 12;45(19):4057-93 - PubMed
  116. J Med Chem. 2010 Apr 22;53(8):3305-19 - PubMed
  117. Thromb Haemost. 2007 May;97(5):847-55 - PubMed
  118. J Med Chem. 2010 Mar 25;53(6):2472-81 - PubMed
  119. Curr Opin Hematol. 2009 Sep;16(5):371-7 - PubMed
  120. Bioorg Med Chem. 2009 Jul 1;17(13):4612-21 - PubMed
  121. J Med Chem. 2005 Nov 3;48(22):7040-8 - PubMed
  122. Neuropharmacology. 1999 Jan;38(1):141-9 - PubMed
  123. Mol Pharmacol. 1996 Aug;50(2):415-23 - PubMed
  124. J Med Chem. 2010 Feb 25;53(4):1799-809 - PubMed
  125. J Med Chem. 2002 Dec 19;45(26):5694-709 - PubMed
  126. Platelets. 2008 Mar;19(2):134-45 - PubMed
  127. Platelets. 2004 May;15(3):131-44 - PubMed
  128. Drug Discov Today. 2010 Jul;15(13-14):570-8 - PubMed
  129. Cardiovasc Ther. 2009 Winter;27(4):259-74 - PubMed
  130. Br J Pharmacol. 1994 Aug;112(4):1151-9 - PubMed
  131. Naunyn Schmiedebergs Arch Pharmacol. 1996 Oct;354(4):491-7 - PubMed
  132. Drug Dev Res. 2000 Apr 1;49(4):253-259 - PubMed
  133. Bioorg Med Chem Lett. 2010 Jul 15;20(14):4104-7 - PubMed
  134. Mol Pharmacol. 2004 Feb;65(2):426-36 - PubMed
  135. J Cell Biochem. 2006 Nov 1;99(4):1165-74 - PubMed
  136. Biochem Pharmacol. 2008 Nov 15;76(10):1201-13 - PubMed
  137. Mol Pharmacol. 1998 Dec;54(6):989-93 - PubMed
  138. J Cell Physiol. 2011 Jan;226(1):46-51 - PubMed
  139. J Med Chem. 1999 Dec 30;42(26):5325-37 - PubMed
  140. Biochem Pharmacol. 2010 Aug 15;80(4):506-11 - PubMed
  141. Biochem Pharmacol. 2004 Nov 15;68(10):1995-2002 - PubMed
  142. Nature. 2009 Jul 30;460(7255):592-8 - PubMed
  143. J Med Chem. 2010 Mar 11;53(5):2010-37 - PubMed
  144. J Cell Sci. 2010 Jul 15;123(Pt 14):2512-20 - PubMed
  145. Endocr Metab Immune Disord Drug Targets. 2008 Dec;8(4):244-54 - PubMed
  146. Nature. 2001 Jan 11;409(6817):202-7 - PubMed

Publication Types

Grant support