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 A2 (TXA2) formation from arachidonic acid (AA) and aggregation in platelets, were investigated. YS-49 and YS-51 (IC50; 32.8 and 39.4 μM respectively) exhibited much stronger inhibitory effects on TXA2 formation than higenamine (IC50; 2.99 mM). The higher inhibitory potencies of YS-49 and YS-51 (IC50: 3.3 and 5.7 μM respectively) than higenamine (IC50: 140 μM) 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 TXA2 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 TXA2 production and AA induced aggregation of platelets. In addition, higenamine, YS-49 and YS-51 were observed directly antagonistic on TXA2 receptor (TP receptors) by displaying inhibitory effects to U46619 (TXA2 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 TXA2 from AA and partly by directly blocking the TP receptor, in addition to the previously reported effects on α2-adrenergic receptor. On the other hand, higenamine is supposed to antagonize AA-induced platelet aggregation by mostly directly blocking the TP receptor.