Chalcones as potent antiplatelet agents and calcium channel blockers

In an effort to continually develop potent antiplatelet agents with vasorel axing and antiinflammatory actions, a novel series of anti inflammatory cha lcones was continually screened to evaluate their antiplatelet and vasorela xing effects. Their structure-activity relationships and mode of action wer e discussed and characterized. A novel series of antiinflammatory chalcones was studied on antiplatelet effect in rabbit washed platelets and human pl atelet-rich plasma (PRP) and vasorelaxing effect in rat thoracic aorta. Ara chidonic acid-induced platelet aggregation was potently inhibited by almost all the chalcone derivatives and 13-15 also had a potent inhibitory effect on cyclooxygenase. The selective chalcones 12-16 tested in human PRP signi ficantly inhibited secondary aggregation induced by adrenaline. In rat thor acic aorta, most of chalcones at high concentration significantly depressed the contractions induced by Ca2+ (1.9 mM) in high K+ (80 mM) medium and th e phasic and tonic contractions caused by norepinephrine (3 muM). In the ra t thoracic aorta, the phenylephrine- and high K+-induced Ca-45(2+) influx w ere both inhibited by a selective chalcone derivative, 14. These results in dicate that the antiplatelet actions of chalcones are mainly mediated throu gh the suppression of cyclooxygenase activity and reduced thromboxane forma tion and their inhibitory effects on the contractile response caused by hig h K+ and norepinephrine in rat thoracic aorta are mainly due to inhibition of Ca2+ influx through both voltage-dependent and receptor-operated Ca2+ ch annels. (C) 2001 Wiley-Liss, Inc.