Agonists and Antagonists for P2 Receptors

  1. Derek J. Chadwick Organizer and
  2. Jamie Goode
  1. Kenneth A. Jacobson,
  2. Stefano Costanzi,
  3. Bhalchandra V. Joshi,
  4. Pedro Besada,
  5. Dae Hong Shin,
  6. Hyojin Ko,
  7. Andrei A. Ivanov and
  8. Liaman Mamedova

Published Online: 7 OCT 2008

DOI: 10.1002/9780470032244.ch6

Purinergic Signalling in Neuron-Glia Interactions: Novartis Foundation Symposium 276

Purinergic Signalling in Neuron-Glia Interactions: Novartis Foundation Symposium 276

How to Cite

Jacobson, K. A., Costanzi, S., Joshi, B. V., Besada, P., Shin, D. H., Ko, H., Ivanov, A. A. and Mamedova, L. (2006) Agonists and Antagonists for P2 Receptors, in Purinergic Signalling in Neuron-Glia Interactions: Novartis Foundation Symposium 276 (eds D. J. Chadwick and J. Goode), John Wiley & Sons, Ltd, Chichester, UK. doi: 10.1002/9780470032244.ch6

Author Information

  1. Molecular Recognition Section, National Institutes of Diabetes & Digestive and Kidney Disease, National Institutes of Health, Bldg 8A, Rm B1A-19, Bethesda, MD 20892-0810, USA

Publication History

  1. Published Online: 7 OCT 2008
  2. Published Print: 21 APR 2006

Book Series:

  1. Novartis Foundation Symposia

Book Series Editors:

  1. Novartis Foundation

ISBN Information

Print ISBN: 9780470018606

Online ISBN: 9780470032244

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Keywords:

  • P2 antagonists and agonists;
  • novel non-nucleotide antagonist of P2 receptors;
  • homology modelling in receptor structure study;
  • P2Y receptor molecular modelling;
  • extracellular purine and pyrimidine nucleotides

Summary

Recent work has identified nucleotide agonists selective for P2Y1, P2Y2 and P2Y6 receptors and nucleotide antagonists selective for P2Y1, P2Y12 and P2X1 receptors. Selective non-nucleotide antagonists have been reported for P2Y1, P2Y2, P2Y6, P2Y12, P2Y13, P2X2/3/P2X3 and P2X7 receptors. For example, the dinucleotide INS 37217 (Up4dC) potently activates the P2Y2 receptor, and the non-nucleotide antagonist A-317491 is selective for P2X2/3/P2X3 receptors. Nucleotide analogues in which the ribose moiety is substituted by a variety of novel ring systems, including conformationally locked moieties, have been synthesized as ligands for P2Y receptors. The focus on conformational factors of the ribose-like moiety allows the inclusion of general modifications that lead to enhanced potency and selectivity. At P2Y1,2,4,11 receptors, there is a preference for the North conformation as indicated with (N)-methanocarba analogues. The P2Y1 antagonist MRS2500 inhibited ADP-induced human platelet aggregation with an IC50 of 0.95 nM. MRS2365, an (N)-methanocarba analogue of 2-MeSADP, displayed potency (EC50) of 0.4 nM at the P2Y1 receptor, with >10 000-fold selectivity in comparison to P2Y12 and P2Y13 receptors. At P2Y6 receptors there is a dramatic preference for the South conformation. Three-dimensional structures of P2Y receptors have been deduced from structure activity relationships (SAR), mutagenesis and modelling studies. Detailed three-dimensional structures of P2X receptors have not yet been proposed.