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Modified diadenosine tetraphosphates with dual specificity for P2Y 1 and P2Y 12 are potent antagonists of ADP‐induced platelet activation
Author(s) -
CHANG H.,
YANACHKOV I. B.,
DIX E. J.,
LI Y. F.,
BARNARD M. R.,
WRIGHT G. E.,
MICHELSON A. D.,
FRELINGER A. L.
Publication year - 2012
Publication title -
journal of thrombosis and haemostasis
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.947
H-Index - 178
eISSN - 1538-7836
pISSN - 1538-7933
DOI - 10.1111/jth.12035
Subject(s) - p2y12 , chemistry , agonist , platelet , platelet activation , p2y receptor , ticagrelor , adenosine diphosphate , receptor , adenosine triphosphate , pharmacology , biochemistry , biophysics , platelet aggregation , medicine , biology , clopidogrel , aspirin
Chang H, Yanachkov IB, Dix EJ, Li YF, Barnard MR, Wright GE, Michelson AD, Frelinger AL 3rd. Modified diadenosine tetraphosphates with dual specificity for P2Y 1 and P2Y 12 are potent antagonists of ADP‐induced platelet activation. J Thromb Haemost 2012; 10: 2573–80. Summary. Background : Diadenosine 5′,5′′′‐P 1 ,P 4 ‐tetraphosphate (Ap 4 A), a natural compound stored in platelet dense granules, inhibits ADP‐induced platelet aggregation. Ap 4 A inhibits the platelet ADP receptors P2Y 1 and P2Y 12 , is a partial agonist of P2Y 12 , and is a full agonist of the platelet ATP‐gated ion channel P2X1. Modification of the Ap 4 A tetraphosphate backbone enhances inhibition of ADP‐induced platelet aggregation. However, the effects of these Ap 4 A analogs on human platelet P2Y 1 , P2Y 12 and P2X1 are unclear. Objective : To determine the agonist and antagonist activities of diadenosine tetraphosphate analogs towards P2Y 1 , P2Y 12 , and P2X1. Methods : We synthesized the following Ap 4 A analogs: P 1 ,P 4 ‐dithiotetraphosphate; P 2 ,P 3 ‐chloromethylenetetraphosphate; P 1 ‐thio‐P 2 ,P 3 ‐chloromethylenetetraphosphate; and P 1 ,P 4 ‐dithio‐P 2 ,P 3 ‐chloromethylenetetraphosphate. We then measured the effects of these analogs on: (i) ADP‐induced platelet aggregation; (ii) P2Y 1 ‐mediated changes in cytosolic Ca 2+ ; (iii) P2Y 12 ‐mediated changes in vasodilator‐stimulated phosphoprotein phosphorylation; and (iv) P2X1‐mediated entry of extracellular Ca 2+ . Results : Ap 4 A analogs with modifications in the phosphate backbone inhibited both P2Y 1 and P2Y 12 , and showed no agonist activity towards these receptors. The dithio modification increased inhibition of P2Y 1 , P2Y 12 , and platelet aggregation, whereas the chloromethylene modification increased inhibition of P2Y 12 and platelet aggregation, but decreased P2Y 1 inhibition. Combining the dithio and chloromethylene modifications increased P2Y 1 and P2Y 12 inhibition. As compared with Ap 4 A, each modification decreased agonist activity towards P2X1, and the dual modification completely eliminated P2X1 agonist activity. Conclusions : As compared with Ap 4 A, tetraphosphate backbone analogs of Ap 4 A have diminished activity towards P2X1 but inhibit both P2Y 1 and P2Y 12 and, with greater potency, inhibit ADP‐induced platelet aggregation. Thus, diadenosine tetraphosphate analogs with dual receptor selectivity may have potential as antiplatelet drugs.