Inhibitory effects of three new synthetic compounds on human platelet aggregation.
Three compounds of the AQ series (benzothienyl-aminoethyl ketone derivatives), i.e. 3178 (benzothienyl-2 N,N-diallyl amino ethyl cetone), 1994 (alpha-benzothienyl-beta-N-morpholino ethyl cetone), and 1989 (benzothienyl-2-beta-N,N-dimethyl amino ethyl cetone) were tested against aggregations triggered by adenosine 5'-diphosphate (ADP), arachidonic acid (AA), paf-acether, thrombin or collagen under different experimental conditions. None of them exhibited a specific inhibitory effect on washed platelets prepared so as to render them specifically sensitive either to ADP, AA or paf-acether. Thus for compound 3178 AQ, the most potent of the three, IC50 values were 2.9 +/- 0.6, 2.9 +/- 1.0 and 4.3 +/- 0.9 uM (means +/- 1 SD of 4 experiments) against ADP, AA or paf-acether respectively. Aggregations triggered by subthreshold concentrations of thrombin were also inhibited by compound 3178 AQ (50 uM) even after washing, showing the persistence of the inhibitory effect. Inhibition was surmountable since addition of a 10 fold greater concentration of thrombin than the subthreshold one induced a full aggregation. When tested on platelet-rich plasma (PRP) higher concentrations of the inhibitors than those used on washed platelets were needed in order to counteract ADP, AA or paf-acether effects. Collagen-induced aggregation was also inhibited by the AQ compounds when tested either in PRP or in whole blood although, in the latter case, high concentrations of the antagonists had to be used. These data show that compounds of the AQ series bear a wide spectrum of activity which makes them potential anti-thrombotic agents.
D000244:Adenosine Diphosphate / Q000494:pharmacology; D016718:Arachidonic Acid; D001095:Arachidonic Acids / Q000494:pharmacology; D006801:Humans; D007700:Kinetics; D010972:Platelet Activating Factor / Q000494:pharmacology; D010974:Platelet Aggregation / Q000187:drug effects*; D013329:Structure-Activity Relationship; D013876:Thiophenes / Q000494:pharmacology*; D013917:Thrombin / Q000502:physiology
D001095:Arachidonic Acids; D010972:Platelet Activating Factor; D013876:Thiophenes; D016718:Arachidonic Acid; C051179:2-(3-(diallylamino)propionyl)benzothiophene; C051180:AQ 1989; C051181:AQ 1994; D000244:Adenosine Diphosphate; D013917:Thrombin