Screening For PAF Receptor Antagonist And Study On Their Anti-angiogenesis Action And Mechanisms

The term angiogenesis generally refers to the development of new blood vessels from pre-existing ones. Deregulation of angiogenesis may lead to pathological conditions such as tumor, chronic inflammatory, diabetic retinopathy etc. Recently platelet activating factor (PAF) has been shown to induce angiogenesis in several researches, and plays a role in angiogenesis dependent diseases such as rheumatoid arthritis and atherosclerosis. So it will have theoretical and clinical significance to study the effects of PAF receptor antagonist on angiogenesis. The objects of this article are to screen for new PAF receptor antagonist, investigate their roles in angiogenesis and explore the possible mechanisms through their actions on macrophage and endothelial cells. The results are as follows:Part 1 Screening for PAF receptor antagonist and observation oftheir anti- inflammation effects in vivo.1. Two potent PAF antagonists, 0916 and 0920, were identified using the rapid screening model: PAF-induced β-glycuronidase release from PMNs.2. The result of MTT assay shown that 0916 and 0920 had no cytotoxic effects on rat polymorphonuclear leukocytes, mice peritoneal macrophages, bovine aortic endothelial cells and L929 cells.3. [³H]-PAF radio-ligand receptor binding assay indicated that there was a single class of PAF receptors (100.2 fmol·10⁶ cells^-1) on the mouse peritoneal macrophage with a dissociation constant (K_D) of 3.2 nmol. Four compounds: 0916, 0920, 322, and BN52021 could competitively inhibit the specific binding of [³H]-PAF to its receptor. Among the compounds tested, 0916 is the most potent, followed by 0920, 322 and BN52021.