Mechanism of action of two new pyrimidoquinoline and isoquinoline derivatives in human platelets.

In the present study the "in vitro" influence of 3-(1-piperazinyl)-1H-pyrimido[1,2-a]quinolin-1-one (AQ11) and 2-(piperazinyl)-4H-pyrimido[2,1-a]isoquinolin-4-one (IQ3b) on human platelet aggregation, cAMP elevation, cytosolic calcium and fibrinogen binding has been investigated. Both drugs inhibited platelet aggregation in a concentration-dependent manner. In PRP AQ11 was slightly more active than IQ3b when aggregation was induced by ADP, collagen, A23187 or PMA, whereas in washed platelets challenged by thrombin, IQ3b was more effective than AQ11. Both compounds produced increase in cAMP intracellular level being the effect potentiated by the adenylate cyclase activator iloprost and IQ3b was more powerful than AQ11. Moreover IQ3b was more effective in inhibiting cAMP in high affinity phosphodiesterase (IC50 values: IQ3b 11 +/- 5 microM; AQ11 43 +/- 8 microM) and calcium elevation (IC50 values: IQ3b 9 +/- 4 microM; AQ11 32 +/- 6 microM). These compounds also inhibited fibrinogen binding in platelets challenged by ADP or thrombin. The results suggest that these new potent agents inhibit platelet phosphodiesterase activity causing an elevation in cAMP levels sufficient to inhibit calcium rise and fibrinogen binding. This mechanism can be responsible for the ability of the compounds to prevent platelet aggregation.

1,5-Benzodiazepines. X. Dialkylamino substituted 1,5-benzodiazepine and [1,2,4]triazolo [4,3-a][1,5] benzodiazepine derivatives with inhibitory activity on PAF-induced platelet aggregation.

Novel 4-(dialkylamino) substituted (4, 5 c, 8) and 2,4-bis(dialkylamino) substituted (6) 1,5-benzodiazepine derivatives were synthesized. Both these new compounds and the substituted 4H-[1,2,4]triazolo[4,3-a][1,5]benzodiazepine-5-amines 2 a-h, recently described by us, were tested in vitro for their inhibitory activity on the PAF-induced aggregation of human platelets. Actually, bicyclic compounds 4 d, 5 c and tricyclic compounds 2 g, h showed a significant activity: in all them the dialkylamino substituent was the 4-(ethoxycarbonyl)-1-piperazinyl group. On the contrary, compounds 4 d, 5 c, 2 g,h showed practically no inhibitory activity when platelet aggregation was induced by ADP, A23187, or collagen.