ys-49 and 1-(beta-naphthylmethyl)-6-7-dihydroxy-1-2-3-4-tetra-hydroisoquinoline

The effects of higenamine and its 1-naphthyl analogs, YS-49 and YS-51, on thromboxane A(2) (TXA(2)) formation from arachidonic acid (AA) and aggregation in platelets, were investigated. YS-49 and YS-51 (IC(50); 32.8 and 39.4 microM respectively) exhibited much stronger inhibitory effects on TXA(2) formation than higenamine (IC(50); 2.99 mM). The higher inhibitory potencies of YS-49 and YS-51 (IC(50): 3.3 and 5.7 microM respectively) than higenamine (IC(50): 140 microM) on AA induced rat platelet aggregation was presumed to be the result of low inhibitory effect of higenamine than YS-49 and YS-51 on TXA(2) production from AA. Among the present three compounds, the more hydrophobic naphthylmethyl groups were supposed to be more favorable than p-hydroxybenzyl moiety, at 1-position of the tetrahydroisoquinoline ring, to display the inhibitory effects on TXA(2) production and AA induced aggregation of platelets. In addition, higenamine, YS-49 and YS-51 were observed directly antagonistic on TXA(2) receptor (TP receptors) by displaying inhibitory effects to U46619 (TXA(2) mimetic) induced platelet aggregation, however all of the three compounds showed similar order of inhibitory potencies. The present results are suggestive that YS-49 and YS-51 exert their inhibitory effects on AA-induced platelet aggregation partly by inhibiting the production of TXA(2) from AA and partly by directly blocking the TP receptor, in addition to the previously reported effects on alpha(2)-adrenergic receptor. On the other hand, higenamine is supposed to antagonize AA-induced platelet aggregation by mostly directly blocking the TP receptor.

Topics: Adult; Alkaloids; Animals; Blood Platelets; Female; Fibrinolytic Agents; Humans; Male; Platelet Aggregation; Rats; Rats, Sprague-Dawley; Tetrahydroisoquinolines; Thromboxane A2; Treatment Outcome

Disseminated intravascular coagulation (DIC) is a pathological syndrome, which occurs following the uncontrolled widespread activation of blood coagulation, resulting in the intravascular formation of fibrin, which may lead to thrombotic occlusion of small and midsize vessels. The effects of 1-(alpha-naphthylmethyl)-6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline (YS-49, CAS 132836-42-1) and 1-(beta-naphthylmethyl)-6,7-dihydroxy-1,2,3,4-tetra-hydroisoquinoline (YS-51, CAS 213179-96-5) on the experimental DIC induced by lipopolysaccharide (LPS) in rats, were investigated. The oral administration of YS-49 and YS-51 (10 or 50 mg/kg) attenuated the dramatic increase of serum fibrinogen/fibrin degradation product (FDP) level, the decrease of plasma fibrinogen concentration and the number of platelets in blood and the prolongation of prothrombin time (PT) and activated partial thromboplastin time (aPTT) induced by LPS. The liver and kidney function parameters, aspartate amino-transferase (AST) and blood urea nitrogen (BUN), were also improved with YS-49 and YS-51. The above results suggest that YS-49 and YS-51 have therapeutic potential for DIC and/or accompanying multiple organ failure.

Topics: Animals; Aspartate Aminotransferases; Blood Urea Nitrogen; Disseminated Intravascular Coagulation; Fibrinogen; Lipopolysaccharides; Male; Partial Thromboplastin Time; Platelet Count; Prothrombin Time; Rats; Rats, Sprague-Dawley; Tetrahydroisoquinolines

The antiplatelet and antithrombotic effects of YS-49 and YS-51--l-naphthylmethyl analogs of higenamine, which is a benzyl-tetrahydroisoquinoline alkaloid isolated from Aconitum japonicum (Ranunculaceae)--were investigated. YS-49 and YS-51 showed inhibitory activities to both human and rat platelet aggregation induced by ADP, collagen and epinephrine. They were more inhibitory to epinephrine-induced aggregation (IC(50); 3.4 and 1.7 microM of YS-49, and 6.0 and 6.3 microM of YS-51 to human and rat platelets, respectively) than ADP- or collagen-induced aggregation. The antithrombotic effects of YS-49 and YS-51 were also observed in both mouse acute thrombosis model and rat arterio-venous shunt (AV shunt) model. The oral administration of YS-49 and YS-51 (50 or 100 mg/kg) increased the recovery rates from the acute thrombotic challenge in mice and lowered the weight of thrombus formed inside the AV shunt tube in rats.

Topics: Alkaloids; Animals; Disease Models, Animal; Fibrinolytic Agents; Humans; Inhibitory Concentration 50; Isoquinolines; Mice; Mice, Inbred ICR; Platelet Aggregation; Platelet Aggregation Inhibitors; Rats; Rats, Sprague-Dawley; Tetrahydroisoquinolines; Thrombosis; Treatment Outcome