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

Br J Pharmacol. 1989 Feb;96(2):291-300. doi: 10.1111/j.1476-5381.1989.tb11816.x.

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 pKB 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 microM 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.

MeSH terms

  • 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid
  • Animals
  • Blood Platelets / drug effects*
  • Blood Vessels / drug effects*
  • Guinea Pigs
  • Humans
  • Hydantoins / antagonists & inhibitors
  • Hydantoins / pharmacology*
  • In Vitro Techniques
  • Jugular Veins / drug effects
  • Male
  • Muscle Contraction / drug effects
  • Platelet Aggregation / drug effects
  • Prostaglandin D2 / antagonists & inhibitors*
  • Prostaglandin Endoperoxides, Synthetic / antagonists & inhibitors
  • Rabbits
  • Receptors, Prostaglandin / drug effects*
  • Sulfonamides / pharmacology
  • Trachea / drug effects

Substances

  • Hydantoins
  • Prostaglandin Endoperoxides, Synthetic
  • Receptors, Prostaglandin
  • Sulfonamides
  • BW A868C
  • sulotroban
  • BW 245C
  • 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid
  • Prostaglandin D2