L-652,469 - a dual receptor antagonist of platelet activating factor and dihydropyridines from Tussilago farfara L

Abstract

L-652,469, 14-acetoxy-7β-(3′-ethylcrotonoyloxy)-notonipetranone, isolated from the methylene chloride extracts of the buds of Tussilago farfara L, was found to inhibit both platelet activating factor (PAF) and Ca 2+ entry blocker binding to membrane vesicles. It inhibits the [ 3H]PAF specific binding to rabbit platelet membranes with equilibrium inhibition constants (K i) of 3.2 and 4.0 μM in the presence of 150 mM NaCl and 10 mM MgCl 2 respectively. It is a competitive PAF receptor antagonist with an equilibrium dissociation constant (K B) of 5.16 μM. It also competitively inhibits the specific binding of Ca 2+ channel blockers (e.g. [ 3H]nitrendipine; K i = 1.2 μM) in cardiac sarcolemmal vesicles. At 10 −5 M, L-652,469 causes a 60% relaxation of Ca 2+-induced contraction of rat thoracic aorta strips. Due to its dual antagonistic activities, L-652,469 potently inhibits the gel-filtered rabbit platelet aggregation with a pA 2 of 5.79. It was also found to be orally active with a beneficial effect to inhibit the PAF-induced rat foot edema and the first phase of carrageenan-induced rat hindpaw edema.