Though antiplatelet drugs are proven beneficial to patients with coronary heart disease and stroke, more effective and safer antiplatelet drugs are still needed. In this study we report the antiplatelet effects and mechanism of BF0801, a novel adenine derivative. BF0801 dramatically inhibited platelet aggregation and ATP release induced by ADP, 2MeSADP, AYPGKF, SFLLRN or convulxin without affecting shape change in vitro. It also potentiated the inhibitory effects of adenosine-based P2Y(12) antagonist AR-C69931MX or phosphodiesterase (PDE) inhibitor IBMX on platelet aggregation. The cAMP levels in both resting and forskolin-stimulated platelets were increased by BF0801 suggesting its PDE inhibitor activity, which is further confirmed by the concentration-dependent suppression of BF0801 on the native and recombinant PDE. Similar to AR-C69931MX, BF0801 drastically inhibited 2MeSADP-induced adenylyl cyclase inhibition in platelets indicating its P2Y(12) antagonism activity, which is substantiated by the inhibition of BF0801 on the interaction between ADP and P2Y(12) receptor expressed in CHO-K1 cells measured by atomic force microscopy. Moreover, we confirmed the antiplatelet effects of BF0801 using platelets from rats intravenously given BF0801. In summary, for the first time we developed a novel adenine derivative bearing dual activities of PDE inhibition and P2Y(12) antagonism, which may have therapeutic advantage as a potential antithrombotic drug.
[1]Fudan Univ, Shanghai Med Coll, Key Lab Mol Med, Minist Educ, Shanghai 200032, Peoples R China.
[2]Fudan Univ, Shanghai Med Coll, Dept Biochem & Mol Biol, Shanghai 200032, Peoples R China.
[3]Beijing Univ Chem Technol, Coll Sci, Beijing, Peoples R China.
[4]Chinese Acad Sci, Shanghai Inst Biol Sci, Inst Biochem & Cell Biol, Shanghai, Peoples R China.
[5]Shanghai Jiao Tong Univ, Sch Med, Inst Med Sci, Shanghai 200030, Peoples R China.
[6]Temple Univ, Sch Med, Dept Physiol, Philadelphia, PA 19122 USA.
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