ONO NT-126 is a potent and selective thromboxane A2 antagonist in human astrocytoma cells.
Stimulation of thromboxane A2 (TXA2) receptors in human astrocytoma cells (1321N1) results in activation of phospholipase C via a pertussis toxin-insensitive G-protein. In the present study, the potency of a new TXA2 receptor antagonist, ONO NT-126, was examined with regard to receptor binding and phosphoinositide hydrolysis in human astrocytoma cells and was compared to that of the other known TXA2 antagonists. [3H]SQ29548 binding to membranes was inhibited by ONO NT-126 and the other TXA2 antagonists with Ki values (nM) of 0.09, 2.18, 8.35 and 25.9 for ONO NT-126, S-145, SQ29548 and ONO3708, respectively. STA2 and U46619, TXA2 receptor agonists, also inhibited [3H]SQ29548 binding with Ki (nM) of 25.1 and 233.5, respectively. STA2 and U46619 stimulated phosphoinositide hydrolysis in a concentration-dependent manner with EC50 values of 43.6 nM for STA2 and 1.2 microM for U46619, respectively. STA2 (1 microM)-induced phosphoinositide hydrolysis was also inhibited by TXA2 antagonists. The Ki values of TXA2 antagonists for the inhibition of phosphoinositide hydrolysis (nM) were 0.10 for ONO NT-126, 3.31 for S-145, 8.31 for SQ29548 and 19.49 for ONO3708 all of which were similar to those for receptor binding. The results indicate that ONO NT-126 is a potent and selective antagonist of TXA2 receptors in human astrocytoma cells.
Nakahata
N
N
Department of Pharmacology, Fukushima Medical College, Japan.
Sato
K
K
Abe
M T
MT
Nakanishi
H
H
D001254:Astrocytoma / Q000378:metabolism; D001643:Bridged Bicyclo Compounds / Q000494:pharmacology*; D019086:Bridged Bicyclo Compounds, Heterocyclic; D005229:Fatty Acids, Monounsaturated / Q000494:pharmacology*; D005231:Fatty Acids, Unsaturated; D006801:Humans; D006834:Hydrazines / Q000378:metabolism; D006868:Hydrolysis; D007295:Inositol Phosphates / Q000032:analysis; D010716:Phosphatidylinositols / Q000378:metabolism; D011869:Radioligand Assay; D011982:Receptors, Prostaglandin / Q000187:drug effects / Q000378:metabolism; D017482:Receptors, Thromboxane; D013928:Thromboxane A2 / Q000037:antagonists & inhibitors*; D014407:Tumor Cells, Cultured
D001643:Bridged Bicyclo Compounds; D019086:Bridged Bicyclo Compounds, Heterocyclic; D005229:Fatty Acids, Monounsaturated; D005231:Fatty Acids, Unsaturated; D006834:Hydrazines; D007295:Inositol Phosphates; D010716:Phosphatidylinositols; D011982:Receptors, Prostaglandin; D017482:Receptors, Thromboxane; C067520:ONO-NT 126; D013928:Thromboxane A2; C045749:SQ 29548