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]pyrimi din-4-one (AP155) was tested in vitro by measuring cyclic adenosine monophosphate (cAMP) level, cytosolic Ca++, [(125I)]fibrinogen binding as well as aggregation induced by several agonists. AP155 dose-dependently inhibited aggregation both in platelet rich plasma (PRP) and in washed platelets (WP), exerting its maximal power in the presence of collagen, ADP and platelet activating factor (PAF). It specifically inhibited the activity of cAMP high affinity phosphodiesterase (PDE), resulting in a sufficient increase in cAMP levels to activate cAMP-dependent protein kinase. AP155 was able to inhibit aggregation, the increase in cytosolic Ca++ induced by thrombin, and fibrinogen binding to ADP or thrombin-stimulated platelets. Thus, this new pyridopyrimidine derivative exerts its antiplatelet activity by increasing cAMP intracellular concentration.
Leoncini
G
G
Istituto di Chimica Biologica, Università di Genova, Italy.
Signorello
M G
MG
Roma
G
G
Di Braccio
M
M
D001792:Blood Platelets / Q000187:drug effects* / Q000378:metabolism; D002118:Calcium / Q000378:metabolism; D000242:Cyclic AMP / Q000032:analysis; D006152:Cyclic GMP / Q000032:analysis; D004305:Dose-Response Relationship, Drug; D005340:Fibrinogen / Q000378:metabolism; D006801:Humans; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology*; D010975:Platelet Aggregation Inhibitors / Q000494:pharmacology*; D011725:Pyridines / Q000494:pharmacology*; D011744:Pyrimidinones / Q000494:pharmacology*; D015398:Signal Transduction
C107646:AP 155; D010726:Phosphodiesterase Inhibitors; D010975:Platelet Aggregation Inhibitors; D011725:Pyridines; D011744:Pyrimidinones; D005340:Fibrinogen; D000242:Cyclic AMP; D006152:Cyclic GMP; D002118:Calcium