Vol. 293, Issue 2, 321-328, May 2000

Affinities, Selectivities, Potencies, and Intrinsic Activities of Natural and Synthetic Prostanoids Using Endogenous Receptors: Focus on DP Class Prostanoids

Najam A. Sharif, Julie Y. Crider, Shouxi X. Xu and Gary W. Williams

Molecular Pharmacology Unit, Alcon Research, Ltd., Fort Worth, Texas

The prostanoid receptor-subtype binding affinities, selectivities, potencies, and intrinsic activities of four natural prostanoids and six synthetic DP class prostanoids were determined using binding and functional assays with endogenous receptors. SQ27986 exhibited the highest affinity for the human platelet DP receptor and the best DP receptor selectivity profile. Prostaglandin (PG)D₂ was the least DP receptor-selective. The rank order of compound affinities at the DP receptor was SQ27986 (K_i = 10 ± 2 nM) > RS93520 = ZK110841 = BW245C (K_i = 23-26 nM) > ZK118182 (K_i = 50 ± 9 nM) > PGD₂ (K_i = 80 ± 5 nM). DP receptor agonists produced cAMP in embryonic bovine tracheal fibroblasts with different potencies (EC₅₀ values in nM): ZK118182 (18 ± 6), RS93520 (28 ± 6), SQ27986 (29 ± 7), ZK110841 (31 ± 7), BW245C (53 ± 16), and PGD₂ (98 ± 10). BW245C was more efficacious and RS93520 was less efficacious than PGD₂. ZK110841 and ZK118182 exhibited a relatively high potency at the adenylyl cyclase-coupled EP₂ receptor in human nonpigmented ciliary epithelial cells but were partial agonists. None of the DP class agonists showed any EP₄ receptor functional activity in Chinese hamster ovary cells. The DP receptor antagonist BWA868C competitively antagonized the PGD₂-induced cAMP accumulation in embryonic bovine tracheal fibroblast cells (pA₂ = 7.83 ± 0.08). The dissociation constants for BWA868C antagonizing PGD₂-, BW245C-, and ZK118182-induced cAMP production were quite similar (apparent log K_b = 7.9-8.2, n = 5-9). The pharmacological properties of some natural and numerous DP class synthetic prostanoids have been determined using endogenous receptors.