Selective antagonism of platelet-activating factor (PAF)-induced aggregation and secretion in washed rabbit platelets by CV-3988, L-652731, triazolam and alprazolam.

Platelet-activating factor (1-O-alkyl-2-acetyl-sn-glycero-3-phosphorylcholine or AGEPC) is a potent phospholipid mediator elaborated by a variety of mammalian cells. CV-3988 (a unique structural analog of AGEPC), L-652731 (a lignan derivative of a natural product) and two triazolobenzodiazepines (triazolam and alprazolam) were evaluated for their ability to selectively antagonize aggregation and secretion responses in washed, [3H]serotonin-labeled rabbit platelets stimulated with graded doses of AGEPC. When 0.2 nM AGEPC was used as the stimulus, the concentration of antagonist needed for 50% inhibition (IC50) of secretion was obtained at 0.05 uM, 0.15 uM, 0.6 uM and 2.5 uM, for L-652732, CV-3988, triazolam and alprazolam, respectively. The corresponding IC50 values for aggregation were obtained at 0.2 uM, 0.1 uM, 1.5 uM and 6.5 uM, respectively. The inhibitory effects could be overcome by increasing the amount of AGEPC used to stimulate the platelets. Of the four compounds tested, L-652731 was the most potent antagonist of AGEPC-induced activation of washed rabbit platelets.