MECHANISM OF ACTION OF 2 NEW PYRIMIDOQUINOLINE AND ISOQUINOLINE DERIVATIVES IN HUMAN PLATELETS

In the present study the ''in vitro'' influence of 3-(1-piperazinyl)-1 H-pyrimido[1,2-a] quinolin-1-one (AQ11) and 1-piperazinyl)-4H-pyrimido [2,1-a]isoquinolin-4-one (IQ3b) on human platelet aggregation, cAMP el evation, cytosolic calcium and fibrinogen binding has been investigate d. Both drugs inhibited platelet aggregation in a concentration-depend ent manner. In PRP AQ11 was slightly more active than IQ3b when aggreg ation was induced by ADP, collagen, A23187 or PMA, whereas in washed p latelets challenged by thrombin, IQ3b was more effective than AQ11. Bo th compounds produced increase in cAMP intracellular level being the e ffect potentiated by the adenylate cyclase activator iloprost and IQ3b was more powerful than AQ11. Moreover IQ3b was more effective in inhi biting cAMP high affinity phosphodiesterase (IC50 values: IQ3b 11+/-5 mu M; AQ11 43+/-8 mu M) and calcium elevation (IC50 values: IQ3b 9+/-4 mu M; AQ11 32+/-6 mu M). These compounds also inhibited fibrinogen bi nding in platelets challenged by ADP or thrombin. The results suggest that these new potent agents inhibit platelet phosphodiesterase activi ty causing an elevation in cAMP levels sufficient to inhibit calcium r ise and fibrinogen binding. This mechanism can be responsible for the ability of the compounds to prevent platelet aggregation. (C) 1997 Els evier Science Ltd.