Antiplatelet Effects of Selected Xanthine-Based Adenosine A[sub.2A] and A[sub.2B] Receptor Antagonists Determined in Rat Blood

The platelet aggregation inhibitory activity of selected xanthine-based adenosine A[sub.2A] and A[sub.2B] receptor antagonists was investigated, and attempts were made to explain the observed effects. The selective A[sub.2B] receptor antagonist PSB-603 and the A[sub.2A] receptor antagonist TB-42 inhibited platelet aggregation induced by collagen or ADP. In addition to adenosine receptor blockade, the compounds were found to act as moderately potent non-selective inhibitors of phosphodiesterases (PDEs). TB-42 showed the highest inhibitory activity against PDE3A along with moderate activity against PDE2A and PDE5A. The antiplatelet activity of PSB-603 and TB-42 may be due to inhibition of PDEs, which induces an increase in cAMP and/or cGMP concentrations in platelets. The xanthine-based adenosine receptor antagonists were found to be non-cytotoxic for platelets. Some of the compounds showed anti-oxidative properties reducing lipid peroxidation. These results may provide a basis for the future development of multi-target xanthine derivatives for the treatment of inflammation and atherosclerosis and the prevention of heart infarction and stroke.