triletide and 1-benzylimidazole

There is accumulating evidence that the presence of the imidazole ring is essential for the inhibition of the thromboxane synthetase activity of several compounds synthetized so far. Inhibition of arachidonic acid (AA) induced platelet aggregation was observed by us with a series of tripeptides in which the imidazole ring belongs to histidine, included in a proper aminoacid sequence. Among these compounds the N-acetyl-L-phenylalanyl-L-phenylalanyl-L-histidine methylester (ZAMI-420) was the most effective. The bioassay of the supernatant of an AA-added platelet-rich plasma (PRP) preparation, preincubated with increasing concentrations of ZAMI-420, showed a dose-related reduction in thromboxane-A2 (TXA2)-like activity, an increase of PG-like response and disappearance of the TXB2 peak in the radiochromatogram; RIA experiments led to the same results. ZAMI-420 does not influence cyclooxygenase activity as the AA-induced increase in O2-consumption by the microsomal fraction of bovine seminal vesicles was unaltered by this compound. Administered orally to the rat, ZAMI-420 was able to prevent gastric damage provoked by a variety of pharmacological agents, including ASA, 5HT and alcohol. The protective effect on experimentally-induced gastric damage is not mediated through the antisecretory properties of this compound but is more likely to be due to a cytoprotective mechanism based on blockade of TXA2 synthesis.

Topics: Animals; Arachidonic Acids; Biological Assay; Carbenoxolone; Chromatography, Thin Layer; Cimetidine; Ethanol; Female; Guinea Pigs; Imidazoles; Oligopeptides; Platelet Aggregation; Prostaglandin-Endoperoxide Synthases; Rabbits; Radioimmunoassay; Rats; Rats, Inbred Strains; Serotonin; Stomach; Stomach Ulcer; Thromboxane A2; Thromboxanes; Vasoconstriction