title: Mechanism of action of two new pyrimidoquinoline and isoquinoline derivatives in human platelets.
abstract: 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.
authors.affiliation: Istituto di Chimica Biologica, Università di Genova, Italy.
authors.forename: G
authors.initials: G
authors.lastname: Leoncini
authors.forename: M G
authors.initials: MG
authors.lastname: Signorello
authors.forename: G C
authors.initials: GC
authors.lastname: Grossi
authors.forename: M
authors.initials: M
authors.lastname: Di Braccio
mesh_terms: D000244:Adenosine Diphosphate / Q000494:pharmacology; D000001:Calcimycin / Q000494:pharmacology; D003094:Collagen / Q000494:pharmacology; D000242:Cyclic AMP / Q000097:blood; D006801:Humans; D007476:Ionophores / Q000494:pharmacology; D007546:Isoquinolines / Q000494:pharmacology*; D010975:Platelet Aggregation Inhibitors / Q000494:pharmacology*; D015363:Quinolones / Q000494:pharmacology*; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology
chemical_list: C108949:2-(1-piperazinyl)-4H-pyrimido(2,1-a)isoquinolin-4-one; C108948:3-(1-piperazinyl)-1H-pyrimido(1,2-a)quinolin-1-one; D007476:Ionophores; D007546:Isoquinolines; D010975:Platelet Aggregation Inhibitors; D015363:Quinolones; D000001:Calcimycin; D000244:Adenosine Diphosphate; D003094:Collagen; D000242:Cyclic AMP; D013755:Tetradecanoylphorbol Acetate