Prehispanolone, a novel platelet activating factor receptor antagonist from Leonurus heterophyllus

1. Using an in vitro radioligand binding assay for the platelet activating factor (PAF) receptor, we have identified a novel, specific PAF antagonist, prehispanolone, from a Chinese medicinal herb Leonurus heterophyllus. 2. The presence of sodium ions inhibited specific [3H]-PAF binding to rabbit platelet membrane with an IC50 of 5.2 mM, decreased the inhibitory potency of PAF but increased the inhibitory potency of prehispanolone. 3. Prehispanolone and several of its derivatives inhibited the binding of [3H]-PAF to rabbit platelets with potencies closely resembling that of inhibition of PAF-induced aggregation. 4. The integrity of the tetrahydrofuran ring of prehispanolone is critical for its interaction with the PAF receptor. 5. By hydrogenating the dihydrofuran ring and replacing the keto group of prehispanolone with a hydroxyl group, we obtained a compound, LC5507, that is more stable and more active than prehispanolone as a PAF receptor antagonist.