Kohler C, Carroll M, Tarrant E, Torley L, Wissner A
Oncology and Inflammation Section, Lederle Labs American Cyanamid Co., Pearl River, New York 10965.
Inflammation. 1993 Jun;17(3):245-61. doi: 10.1007/BF00918988.
Several 1-alkyl ether lipids were studied for their ability to inhibit PLA2 and antagonize PAF responses. Studies with synthetic micellar substrate (1-stearyl-2-arachidonyl phosphocholine), at concentrations ranging from 0.02 to 1000 microM, demonstrate that CL 118326 inhibits porcine pancreatic PLA2 in vitro. As the substrate concentration increases, there is a dose-dependent increase in the IC50 value (IC50 ranges: 1.6-84.6 micrograms/ml or 2.6-137 microM). CL 118326 inhibits mammalian pancreatic PLA2, but not snake or bee venom PLA2. CL 118326 inhibits thrombin (IC50 = 7.9 microM), but not Na arachidonate- (IC50 > 100 microM) induced platelet aggregation, indicative of inhibition of cellular PLA2. CL 118326 inhibits other PLA2-dependent processes such as antigen-induced leukotriene (LTC4) release (IC50 = 2.3 micrograms/ml or 3.8 microM) and histamine release (IC50 = 1.4 micrograms/ml or 2.2 microM) in basophil-enriched WBCs. Intradermal coinjection of CL 118326 (10 micrograms) with PLA2 into guinea pig skin inhibits pancreatic PLA2-induced increase in vascular permeability and leakage, but not snake or bee venom PLA2-induced leakage. CL 118326 shows no PAF-like agonist activity in stimulating rabbit platelet-rich plasma. It inhibits PAF-induced aggregation (IC50 = 5.8 microM), but not ADP-induced aggregation. CL 118326 has greater efficacy as a PLA2 inhibitor than as a PAF antagonist since the IC50-substrate concentration ratio for PLA2 inhibition is < or = 1.0 at substrate concentrations of 10-1000 microM while the IC50-agonist ratio for PAF antagonism is > 100. Results for four other compounds related to CL 118326 are also presented.
研究了几种1-烷基醚脂质抑制磷脂酶A2（PLA2）和拮抗血小板活化因子（PAF）反应的能力。使用合成胶束底物（1-硬脂酰-2-花生四烯酰磷脂酰胆碱），在0.02至1000微摩尔浓度范围内进行的研究表明，CL 118326在体外可抑制猪胰PLA2。随着底物浓度增加，IC50值呈剂量依赖性增加（IC50范围：1.6 - 84.6微克/毫升或2.6 - 137微摩尔）。CL 118326可抑制哺乳动物胰PLA2，但不抑制蛇毒或蜂毒PLA2。CL 118326可抑制凝血酶（IC50 = 7.9微摩尔），但不抑制花生四烯酸钠（IC50 > 100微摩尔）诱导的血小板聚集，这表明其对细胞PLA2有抑制作用。CL 118326可抑制其他依赖PLA2的过程，如抗原诱导的富含嗜碱性粒细胞的白细胞中白三烯（LTC4）释放（IC50 = 2.3微克/毫升或3.8微摩尔）和组胺释放（IC50 = 1.4微克/毫升或2.2微摩尔）。在豚鼠皮肤中，将CL 118326（10微克）与PLA2皮内联合注射可抑制胰PLA2诱导的血管通透性增加和渗漏，但不抑制蛇毒或蜂毒PLA2诱导的渗漏。CL 118326在刺激富含兔血小板的血浆时未表现出PAF样激动剂活性。它可抑制PAF诱导的聚集（IC50 = 5.8微摩尔），但不抑制ADP诱导的聚集。由于在10 - 1000微摩尔底物浓度下，CL 118326抑制PLA2的IC50与底物浓度之比≤1.0，而其拮抗PAF的IC50与激动剂之比>100，因此CL 118326作为PLA2抑制剂比作为PAF拮抗剂更有效。还给出了与CL 118326相关的其他四种化合物的结果。
