Dual antagonism by L-636,499 of serotonin and thromboxane A2 induced aggregation of canine platelets.
We evaluated the ability of L-636,499 (3-carboxyl-dibenzo-[b,f] thiepen-5,5-dioxide), a compound structurally similar to cyproheptadine, to antagonize U46619 (a TXA2/PGH2 mimetic) and serotonin (5-hydroxytryptamine; 5HT)-induced aggregation of canine platelets in vitro. L-636,499 antagonized competitively and dose-dependently aggregation induced by both 5HT and U46619, with pA2 values of 5.8 +/- 0.6 and 4.8 +/- 0.2, respectively. L-670,596, a potent TXA2/PGH2 receptor antagonist, and ketanser in, a potent 5HT2 receptor antagonist, yielded pA2 values of 7.0 +/- 0.3 and 9.0 +/- 0.2 vs. their respective agonists. These results show that despite its low potency vs. TXA2- and 5HT2-induced aggregation, L-636,499 antagonizes both physiologic mediators comparably.
Siegfried
M E
ME
Department of Pharmacology, Merck Sharp & Dohme Research Laboratories, West Point, Pennsylvania 19486.
Bush
L R
LR
D000818:Animals; D002227:Carbazoles / Q000494:pharmacology; D003988:Dibenzothiepins / Q000494:pharmacology*; D004285:Dogs; D066298:In Vitro Techniques; D007650:Ketanserin / Q000494:pharmacology; D008297:Male; D015394:Molecular Structure; D010975:Platelet Aggregation Inhibitors; D011450:Prostaglandin Endoperoxides, Synthetic / Q000494:pharmacology; D012702:Serotonin Antagonists; D013928:Thromboxane A2 / Q000037:antagonists & inhibitors*
D002227:Carbazoles; D003988:Dibenzothiepins; D010975:Platelet Aggregation Inhibitors; D011450:Prostaglandin Endoperoxides, Synthetic; D012702:Serotonin Antagonists; C061299:L 670596; D013928:Thromboxane A2; C047685:L 636499; D007650:Ketanserin