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Journal of Pharmacology And Experimental Therapeutics Fast Forward
First published on October 19, 2005; DOI: 10.1124/jpet.105.094037

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Received for publication August 9, 2005.
Revised October 13, 2005.
Accepted for publication October 17, 2005.

MRS2500, a potent, selective and stable antagonist of the P2Y1 receptor, with strong antithrombotic activity in mice

Beatrice Hechler 1, Christelle Nonne 1, Eun Joo Roh 2, Marco Cattaneo 3, Jean-Pierre Cazenave 1, Francois Lanza 1, Kenneth Jacobson 2, Christian Gachet 4*

1 INSERM U.311, Strasbourg, France 2 Molecular Recognition Section, National Institutes of Health, Bethesda, MD, USA 3 Unita di Ematologia e Trombosi, Ospedale San Paolo, DMCO, Universita di Milano, Italy 4 INSERM U.311, Strasbourg France

* Address correspondence to: E-mail: christian.gachet{at}efs-alsace.fr

Abstract

The platelet P2Y1 ADP receptor is an attractive target for new antiplatelet drugs. However, due to the lack of strong and stable antagonists, only a few studies have suggested that pharmacological inhibition of the P2Y1 receptor could efficiently inhibit experimental thrombosis in vivo. Our aim was to determine whether the newly described potent and selective P2Y1 receptor antagonist MRS2500 (2-iodo-N6-methyl-(N)-methanocarba-2'-deoxyadenosine-3',5'-bisphosphate) could inhibit platelet function ex vivo and experimental thrombosis in mice in vivo. MRS2500 was injected intravenously into mice and its effect on ex vivo platelet aggregation and in several models of thrombosis in vivo was determined. MRS2500 displayed high potency, stable and selective P2Y1 receptor inhibition ex vivo. Although MRS2500 injection resulted in only moderate prolongation of the bleeding time, it provided strong protection in systemic thromboembolism induced by infusion of a mixture of collagen and adrenaline. MRS2500 also potently inhibited localized arterial thrombosis in a model of laser-induced vessel wall injury with two degrees of severity. Moreover, combination of MRS2500 with clopidogrel, the irreversible inhibitor of the platelet P2Y12 receptor for ADP, led to increased antithrombotic efficacy as compared to each alone. These results add further evidence for a role of the P2Y1 receptor in thrombosis and validate the concept that targeting the P2Y1 receptor could be a relevant alternative or complement to current antiplatelet strategies.


Key words: Haemostasis, P2 receptor, mouse, nucleotides, platelet, thrombosis


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