Functional pharmacology of human prostanoid EP 2 and EP 4 receptors

Abstract

Prostanoid EP 2 and EP 4 receptor-mediated responses are difficult to distinguish pharmacologically because of the lack of potent, selective antagonists. We describe systematic agonist fingerprints for recombinant human prostanoid EP 2 and EP 4 receptors expressed in CHO and HEK293 cells, respectively. The rank orders of potency of endogenous prostaglandins were: prostanoid EP 2 receptors: prostaglandin E 2≫prostaglandin D 2=prostaglandin F 2α>prostaglandin I 2; prostanoid EP 4 receptors: prostaglandin E 2≫prostaglandin I 2>prostaglandin D 2=prostaglandin F 2α. Butaprost free acid (9-oxo-11α,16 R-dihydroxy-17-cyclobutyl-prost-13 E-en-1-oic acid) behaved as a highly selective partial agonist at prostanoid EP 2 receptors while butaprost methyl ester elicited small, low potency responses. The prostanoid EP 1 and EP 3 receptor agonists misoprostol (9-oxo-11α,16-dihydroxy-16-methyl-prost-13 E-en-1-oic acid, methyl ester), sulprostone ( N-(methylsulphonyl)-9-oxo-11α,15 R-dihydroxy-16-phenoxy-17,18,19,20-tetranor-prosta-5 Z,13 E-dien-1-amide), and GR63799X ([1 R-[1α( Z),2β( R*),3α]-(-)-4-benzoylamino)phenyl-7-[3-hydroxy-3-phenoxy-propoxy)-5-oxocyclopentyl]-4-heptenoate), and the prostanoid DP receptor agonist BW245C ((4 S)-(3-[(3 R, S)-3-cyclohexyl-3-hydropropyl]-2,5-dioxo)-4-imidazolidineheptanoic acid), activated both prostanoid EP 2 and EP 4 receptors. Prostaglandin I 2, iloprost (6,9α-methylene-11α,15 S-dihydroxy-16-methyl-prosta-5 E,13 E-dien-18-yn-1-oic acid, trometamol salt) and cicaprost (5-[( E)-(1 S, 5 S, 6 S, 7 R)-7-hydroxy-6-[(3 S, 4 S)-3-hydroxy-4-methylnona-1,6-diinyl]-bicyclo[3.3.0]octan-3-yliden]-3-oxapentanoic acid; ZK96480) were full agonists at prostanoid EP 4 receptors. Key differentiating agonists are: butaprost FA, 16,16-dimethyl-prostaglandin E 2, 19-( R)-hydroxy prostaglandin E 2, misoprostol, BW245C, prostaglandin F 2α and prostaglandin D 2.