A new anti-platelet drug, E5510, has multiple suppressive sites during receptor-mediated signal transduction in human platelets.
The mode of action of E5510, 4-cyano-5,5-bis(4-methoxyphenyl)-4-pentenoic acid, which has very potent anti-platelet activities, was investigated by examining its effects on the biochemical responses in the process of human platelet activation. In a whole-cell system, E5510 inhibited the increased turnover of inositol phospholipids arising from phospholipase C activation, arachidonic acid release from phospholipids by phospholipase A2, mobilization of intracellular free Ca2+, protein kinase C activation, and thromboxane A2 production. In a cell-free system, E5510 inhibited cyclooxygenase activity and cyclic AMP-dependent phosphodiesterase activity in a dose-dependent manner. An elevation of cyclic AMP in platelets was also observed at a relatively high concentration of E5510. It was suggested that receptor-mediated turnover of inositol phospholipids, intracellular Ca2+ increase, arachidonic acid release from phospholipids and protein kinase C activation might be indirectly inhibited by the increased cyclic AMP level in platelets. Thromboxane A2 production in the whole-cell system was very strongly inhibited by E5510, and the IC50 for this effect was 100 times lower than that of direct inhibition of cyclooxygenase in the cell-free system. It was concluded that although the primary mode of action of E5510 is the inhibition of the cyclooxygenase pathway of positive signal transduction in platelets, E5510 has another mode of action by increasing platelet cyclic AMP, which can act as a negative messenger in platelet signal transduction, and these multiple sites of action synergistically antagonize platelet cellular activation.
Fujimori
T
T
Eisai Research Laboratories of Tsukuba, Eisai Co., Ltd., Ibaraki, Japan.
Harada
K
K
Saeki
T
T
Kogushi
M
M
Yoshimura
T
T
Katayama
K
K
D016718:Arachidonic Acid; D001095:Arachidonic Acids / Q000097:blood; D001665:Binding Sites / Q000502:physiology; D001792:Blood Platelets / Q000187:drug effects* / Q000378:metabolism; D002118:Calcium / Q000097:blood; D002250:Carbon Radioisotopes; D000242:Cyclic AMP / Q000097:blood; D005229:Fatty Acids, Monounsaturated / Q000494:pharmacology*; D016257:Fura-2; D006801:Humans; D008297:Male; D010741:Phospholipases A / Q000097:blood; D054467:Phospholipases A2; D010727:Phosphoric Diester Hydrolases / Q000097:blood; D010766:Phosphorylation; D010975:Platelet Aggregation Inhibitors / Q000494:pharmacology*; D011451:Prostaglandin-Endoperoxide Synthases / Q000097:blood; D011956:Receptors, Cell Surface / Q000502:physiology*; D015398:Signal Transduction / Q000187:drug effects*; D013917:Thrombin / Q000502:physiology; D013929:Thromboxane B2 / Q000096:biosynthesis
D001095:Arachidonic Acids; D002250:Carbon Radioisotopes; D005229:Fatty Acids, Monounsaturated; D010975:Platelet Aggregation Inhibitors; D011956:Receptors, Cell Surface; D016718:Arachidonic Acid; D013929:Thromboxane B2; D000242:Cyclic AMP; D011451:Prostaglandin-Endoperoxide Synthases; D010741:Phospholipases A; D054467:Phospholipases A2; D010727:Phosphoric Diester Hydrolases; D013917:Thrombin; D002118:Calcium; D016257:Fura-2; C054678:Satigrel