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

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Abstract
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 pKB of 9.26. 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. 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. 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. 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. 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.