Classification of platelet and vascular prostaglandin D2 (DP) receptors: estimation of affinities and relative efficacies for a series of novel bicyclic ligands. With an appendix on goodness-of-fit analyses.
1. The DP receptors located on platelets and vasculature were examined in a human washed platelet preparation and in isolated rings of rabbit external jugular vein. 2. A series of eight novel bicyclic compounds were studied for their effects in the two assays. Seven produced agonism, inhibition of aggregation or vascular relaxation, and one compound was 'silent' in both assays. 3. The operational model of agonism (Black & Leff, 1983) was fitted simultaneously to concentration-effect curve data for the seven agonist compounds. The affinity and efficacy estimates so obtained were tested for similarity between the two tissues by analysis of variance, showing that the model could be fitted to both sets of data by assuming the same relative affinity and efficacy values. However, absolute affinity estimates were consistently lower in the vascular preparation. 4. Analysis of two of the seven agonists as antagonists was also possible. This provided pKB estimates which supported the agonist affinity estimates. The eighth compound was also analysed as an antagonist. It, like the other seven, demonstrated a difference in affinity between the two tissues. 5. The results of this study support the view that platelet and vascular DP receptors are similar, assuming that the systematic difference in affinity estimates for the series of compounds between the two tissues is the consequence of receptor micro-environment and/or accessory binding site differences.
Leff
P
P
Analytical Pharmacological Group, Wellcome Research Laboratories, Beckenham, Kent.
Giles
H
H
D000465:Algorithms; D000818:Animals; D001792:Blood Platelets / Q000737:chemistry*; D001808:Blood Vessels / Q000737:chemistry*; D001643:Bridged Bicyclo Compounds / Q000494:pharmacology*; D006801:Humans; D007601:Jugular Veins / Q000737:chemistry; D015233:Models, Statistical; D011453:Prostaglandins / Q000494:pharmacology; D011817:Rabbits; D011971:Receptors, Immunologic; D011982:Receptors, Prostaglandin / Q000145:classification*
D001643:Bridged Bicyclo Compounds; D011453:Prostaglandins; D011971:Receptors, Immunologic; D011982:Receptors, Prostaglandin; C036293:prostaglandin D2 receptor