Pharmacological Studies Of Leukotriene Synthesis Inhibitors And Receptor Antagonists

This study began with an effort of developing an improved reverse-phase high-performance liquid chromatography (RP-HPLC) procedure to separate and quantitate several leukotrienes (LTs) simultaneously. The production of LTs by rat peritoneal leukocytes following stimulation with A₂₃₁₈₇ and AA. Among several decades of natural and synthetic compounds, Baicalin (BCL), Esculetin, GL-2 and Gossypol were found to inhibit the biosynthesis of LTs. Further studies were performed to investigate the effect of BCL on the postmembrane signal transduction pathways in the rat PMNLs. The results showed that BCL inhibited the increased intracellular Ca²⁺ induced by fMLP and increased the cAMP level in these cells. These results suggest that the inhibitory effect of BCL on LTs biosynthesis might be mediated by a decrease in Ca²⁺ influx and an increase in cAMP level.Using guinea pig lung membrane as experimental material, and ³H-LTC₄ and ³H-LTD₄ as radio ligands, we here studied the characteristics of LTC₄ and LTD₄ receptors. It was found that the binding of ³H-LTC₄ and ³H-LTD₄ was specific, saturable and reversable. The Ki and Bmax values were 27.0×10^-11 mol/L and 355.1 fmol/mg protein for ³H-LTC₄; 19. 9×10^-11mol/L and 232.9 fmol/mg protein for ³H-LTD₄ respectively at 30℃. We have screened more than 80 natural and synthetic compounds and found that there were three seleno-organic compounds (Se9001, Se9005 and Se9006) and one new compound GL-3 (extracted from Gnetum parvifolium), which inhibit ³H-LTC₄ and ³H-LTD₄ binding...