The platelet-activating factor receptor antagonist L-659,989 inhibits phospholipase D activity

The platelet-activating factor (PAF) receptor antagonist L-659,989 [(+/-)-t rans-2-(3-methoxy-5-methylsulfonyl-4-propoxyphenyl)-5-(3,4,5-trimethoxyphen yl)tetrahydrofuran)] has been reported to be a specific inhibitor of the PA F receptor and as such, it is widely used for assessment of PAF receptor me diated biological effects. We report here that L-659,989 may not be as spec ific as previously reported because it is also a potent inhibitor of phosph olipase D activity. At concentrations of 30 mu g/ml, L-659,989 inhibited ba sal and agonist-stimulated phospholipase D activity by about 55% and 70-100 % respectively, through a mechanism that may involve the generation of intr acellular ceramides. Another PAF receptor antagonist, WEB-2086, did not aff ect phospholipase D activity at concentrations up to 50 mu g/ml. Either of these inhibitors when present at 20 mu g/ml are resorted to fully block the effects of PAF. Furthermore, L-659,989 directly inhibited the activity of bacterial PLD in vitro. These results indicate that caution is required in the interpretation of results derived from the use of L-659,989. (C) 1999 E lsevier Science B.V. All rights reserved.