Effects of higenamine and its 1-naphthyl analogs, YS-49 and YS-51, on platelet TXA2 synthesis and aggregation.

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.