Functional pharmacology of human prostanoid EP2 and EP4 receptors.
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(2alpha)>prostaglandin I(2); prostanoid EP(4) receptors: prostaglandin E(2)>>prostaglandin I(2)>prostaglandin D(2)=prostaglandin F(2alpha). Butaprost free acid (9-oxo-11alpha,16R-dihydroxy-17-cyclobutyl-prost-13E-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-11alpha,16-dihydroxy-16-methyl-prost-13E-en-1-oic acid, methyl ester), sulprostone (N-(methylsulphonyl)-9-oxo-11alpha,15R-dihydroxy-16-phenoxy-17,18,19,20-tetranor-prosta-5Z,13E-dien-1-amide), and GR63799X ([1R-[1alpha(Z),2beta(R*),3alpha]-(-)-4-benzoylamino)phenyl-7-[3-hydroxy-3-phenoxy-propoxy)-5-oxocyclopentyl]-4-heptenoate), and the prostanoid DP receptor agonist BW245C ((4S)-(3-[(3R,S)-3-cyclohexyl-3-hydropropyl]-2,5-dioxo)-4-imidazolidineheptanoic acid), activated both prostanoid EP(2) and EP(4) receptors. Prostaglandin I(2), iloprost (6,9alpha-methylene-11alpha,15S-dihydroxy-16-methyl-prosta-5E,13E-dien-18-yn-1-oic acid, trometamol salt) and cicaprost (5-[(E)-(1S, 5S, 6S, 7R)-7-hydroxy-6-[(3S, 4S)-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(2alpha) and prostaglandin D(2).
Receptor Pharmacology Unit, Department of In-vitro Pharmacology, GlaxoSmithKline Medicines Research Center, Gunnels Wood Road, Stevenage, Herts SG1 2NY, UK. rich.j.wilson@gsk.com
Richard J
RJ
Wilson
Sharron A
SA
Rhodes
Richard L
RL
Wood
Vanessa J
VJ
Shield
L Staton
LS
Noel
David W
DW
Gray
Heather
H
Giles
D002460:Cell Line; D000242:Cyclic AMP / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D006801:Humans; D011453:Prostaglandins / Q000494:pharmacology; D018078:Receptors, Prostaglandin E / Q000819:agonists* / Q000502:physiology*; D058307:Receptors, Prostaglandin E, EP2 Subtype; D058309:Receptors, Prostaglandin E, EP4 Subtype
C545644:PTGER2 protein, human; C545650:PTGER4 protein, human; D011453:Prostaglandins; D018078:Receptors, Prostaglandin E; D058307:Receptors, Prostaglandin E, EP2 Subtype; D058309:Receptors, Prostaglandin E, EP4 Subtype; D000242:Cyclic AMP