The classification of prostaglandin DP‐receptors in platelets and vasculature using BW A868C, a novel, selective and potent competitive antagonist

Abstract

1 BW A868C, a novel compound, behaved as a simple competitive antagonist in a human washed platelet aggregation assay. Anti-aggregatory concentration-effect curves to BW 245C were displaced in a parallel manner. The shifts accorded with a Schild plot slope of unity and a pK_B of 9.26. 2 Inhibition of platelet aggregation by prostaglandin D₂ (PGD₂) was antagonized with a similar potency, as were the relaxation effects of BW 245C and PGD₂ in the rabbit jugular vein. BW A868C can, therefore, be classified as a DP-receptor antagonist. 3 Actions of BW A868C at other prostaglandin receptors (IP, EP₁, EP₂, TP and FP) were excluded at concentrations up to 1,000 times higher than the DP-receptor affinity. 4 Analyses of BW 245C- and PGD₂-mediated effects were complicated by additional agonist receptor interactions which were revealed by BW A868C. In rabbit jugular vein a resistant phase of agonism was detectable, indicating that both agonists exerted effects through another receptor (possibly EP₂). Also, PGD₂, in addition to its anti-aggregatory effect on platelets, demonstrated a pro-aggregatory action in the presence of BW A868C. 5 The contractile effects of PGD₂ in guinea-pig tracheal strips were resistant to 10 μm BW A868C indicating that they were not mediated through DP-receptors. 6 To our knowledge this is the first account of a well-classified competitive antagonist at the DP-receptor. Its potency and selectivity make it an important new tool in prostanoid receptor classification and identification.