EFFECT OF 2-(1-PIPERAZINYL)-4H-PYRIDO[1,2-A]PYRIMIDIN-4-ONE (AP155) ON HUMAN PLATELETS IN-VITRO

The effect on human platelets of 2-(1-piperazinyl)-4H-pyrido[1,2-a]pyr imidin-4-one (AP155) was tested in vitro by measuring cyclic adenosine monophosphate (cAMP) level, cytosolic Ca++, [I-125]fibrinogen binding as well as aggregation induced by several agonists. AP155 dose-depend ently inhibited aggregation both in platelet rich plasma (PRP) and in washed platelets (WP), exerting its maximal power in the presence of c ollagen, ADP and platelet activating factor (PAF). It specifically inh ibited the activity of cAMP high affinity phosphodiesterase (PDE), res ulting in a sufficient increase in cAMP levels to activate cAMP-depend ent protein kinase. AP155 was able to inhibit aggregation, the increas e in cytosolic Ca++ induced by thrombin, and fibrinogen binding to ADP or thrombin-stimulated platelets. Thus, this new pyridopyrimidine der ivative exerts its antiplatelet activity by increasing cAMP intracellu lar concentration. BIOCHEM PHARMACOL 53;11: 1667-1672, 1997. (C) 1997 Elsevier Science Inc.