The classification of prostaglandin DP-receptors in platelets and vasculature using BW A868C, a novel, selective and potent competitive antagonist.
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.
Giles
H
H
Department of Pharmacology, Wellcome Research Laboratories, Beckenham, Kent.
Leff
P
P
Bolofo
M L
ML
Kelly
M G
MG
Robertson
A D
AD
D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; D000818:Animals; D001792:Blood Platelets / Q000187:drug effects*; D001808:Blood Vessels / Q000187:drug effects*; D006168:Guinea Pigs; D006801:Humans; D006827:Hydantoins / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D066298:In Vitro Techniques; D007601:Jugular Veins / Q000187:drug effects; D008297:Male; D009119:Muscle Contraction / Q000187:drug effects; D010974:Platelet Aggregation / Q000187:drug effects; D015230:Prostaglandin D2 / Q000037:antagonists & inhibitors*; D011450:Prostaglandin Endoperoxides, Synthetic / Q000037:antagonists & inhibitors; D011817:Rabbits; D011982:Receptors, Prostaglandin / Q000187:drug effects*; D013449:Sulfonamides / Q000494:pharmacology; D014132:Trachea / Q000187:drug effects
D006827:Hydantoins; D011450:Prostaglandin Endoperoxides, Synthetic; D011982:Receptors, Prostaglandin; D013449:Sulfonamides; C058848:BW A868C; C040624:sulotroban; C030669:BW 245C; D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; D015230:Prostaglandin D2