Effect of a series of 1-alkyl ether lipids on inhibition of phospholipase A2 activity and PAF responses.

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.