Semin Thromb Hemost 2005; 31(2): 205-216
DOI: 10.1055/s-2005-869526
Published in 2005 by Thieme Medical Publishers, Inc., 333 Seventh Avenue, New York, NY 10001, USA. Tel: +1(212) 584-4662.

Molecular Recognition at Adenine Nucleotide (P2) Receptors in Platelets

Kenneth A. Jacobson1 , 2 , Liaman Mamedova2 , Bhalchandra V. Joshi2 , Pedro Besada2 , Stefano Costanzi2
  • 1Chief, Molecular Recognition Section, Laboratory of Bioorganic Chemistry, National Institute of Diabetes & Digestive & Kidney Diseases, National Institutes of Health, Bethesda, Maryland
  • 2Molecular Recognition Section, Laboratory of Bioorganic Chemistry, National Institute of Diabetes & Digestive & Kidney Diseases, National Institutes of Health, Bethesda, Maryland
Further Information

Publication History

Publication Date:
26 April 2005 (online)

ABSTRACT

Transmembrane signaling through P2Y receptors for extracellular nucleotides controls a diverse array of cellular processes, including thrombosis. Selective agonists and antagonists of the two P2Y receptors present on the platelet surface-the Gq-coupled P2Y1 subtype and the Gi-coupled P2Y12 subtype-are now known. High-affinity antagonists of each have been developed from nucleotide structures. The (N)-methanocarba bisphosphate derivatives MRS2279 and MRS2500 are potent and selective P2Y1 receptor antagonists. The carbocyclic nucleoside AZD6140 is an uncharged, orally active P2Y12 receptor antagonist of nM affinity. Another nucleotide receptor on the platelet surface, the P2X1 receptor, the activation of which may also be proaggregatory, especially under conditions of high shear stress, has high-affinity ligands, although high selectivity has not yet been achieved. Although α,β-methylene-adenosine triphosphate (ATP) is the classic agonist for the P2X1 receptor, where it causes rapid desensitization, the agonist BzATP is among the most potent in activating this subtype. The aromatic sulfonates NF279 and NF449 are potent antagonists of the P2X1 receptor. The structures of the two platelet P2Y receptors have been modeled, based on a rhodopsin template, to explain the basis for nucleotide recognition within the putative transmembrane binding sites. The P2Y1 receptor model, especially, has been exploited in the design and optimization of antagonists targeted to interact selectively with that subtype.

REFERENCES

 Dr.
Kenneth Jacobson

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, Bethesda, MD 20892-0810

Email: kajacobs@helix.nih.gov

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