MK 287 - A POTENT, SPECIFIC, AND ORALLY-ACTIVE RECEPTOR ANTAGONIST OFPLATELET-ACTIVATING-FACTOR

MK 287 (L-680,573), a tetrahydrofuran analog, potently inhibited [H-3] C18-PAF binding to human platelet, polymorphonuclear leukocyte (PMN) a nd lung membranes with K1 values of 6.1 +/- 1.5, 3.2 +/- 0.7, and 5.49 +/- 2.3 nM, respectively. The inhibitory effects are stereospecific a nd competitive. The racemate, L-668,750 is less potent and the enantio mer, L-680,574 is 20-fold less potent than MK 287. Inhibition of the b inding of [H-3]C18-PAF to human PMN membranes by MK 287 was associated with the reduction of the affinity of the radioligand but not the num ber of the receptor sites. Binding of other radioligands (e.g., LTB4, LTC4, C5a, FMLP) to their specific receptors was unaltered at 1-10 muM MK 287. [H-3]MK 287 bound to membranes from human platelets and PMNs: K(D) = 2.1 +/- 0.6 and 2.9 +/- 1.2 nM, respectively. When examined on isolated human cells, MK 287 potently and selectively inhibited PAF-i nduced aggregation of platelets in plasma (ED50 = 56 +/- 38 nM) or gel -filtered platelets (ED50 = 1.5 +/- 0.5 nM) and elastase release from PMNs (ED50 = 4.4 +/- 2.6 nM). In studies in vivo, MK 287 inhibited PAF -induced lethality in mice (ED50 = 0.8 mg/kg orally) and PAF-induced b ronchoconstriction in guinea pigs (ED50 = 0.18 mg/kg intraduodenally a nd 0.19 mg/kg intravenously). Inhibition of PAF-induced bronchoconstri ction was accompanied by parallel rightward shifts in concentration-re sponse curves for PAF-induced platelet aggregation measured ex vivo.