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The classification of prostaglandin DP‐receptors in platelets and vasculature using BW A868C, a novel, selective and potent competitive antagonist
Author(s) -
Giles Heather,
Leff P.,
Bolofo Mary L.,
Kelly M.G.,
Robertson A.D.
Publication year - 1989
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1111/j.1476-5381.1989.tb11816.x
Subject(s) - receptor , agonist , chemistry , antagonist , prostanoid , schild regression , prostaglandin , prostaglandin e2 receptor , competitive antagonist , pharmacology , partial agonist , prostaglandin d2 , receptor antagonist , potency , medicine , endocrinology , biochemistry , biology , in vitro
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 D 2 (PGD 2 ) was antagonized with a similar potency, as were the relaxation effects of BW 245C and PGD 2 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, EP 1 , EP 2 , TP and FP) were excluded at concentrations up to 1,000 times higher than the DP‐receptor affinity. 4 Analyses of BW 245C‐ and PGD 2 ‐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 EP 2 ). Also, PGD 2 , 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 PGD 2 in guinea‐pig tracheal strips were resistant to 10 μ m 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.