title: Binding and activity of the prostacyclin receptor (IP) agonists, treprostinil and iloprost, at human prostanoid receptors: treprostinil is a potent DP1 and EP2 agonist.
abstract: The prostacyclin analogues, iloprost and treprostinil are extensively used in treating pulmonary hypertension. Their binding profile and corresponding biochemical cellular responses on human prostanoid receptors expressed in cell lines, have now been compared. Iloprost had high binding affinity for EP1 and IP receptors (Ki 1.1 and 3.9 nM, respectively), low affinity for FP, EP3 or EP4 receptors, and very low affinity for EP2, DP1 or TP receptors. By contrast, treprostinil had high affinity for the DP1, EP2 and IP receptors (Ki 4.4, 3.6 and 32 nM, respectively), low affinity for EP1 and EP4 receptors and even lower affinity for EP3, FP and TP receptors. In functional assays, iloprost had similar high activity in elevating cyclic AMP levels in cells expressing the human IP receptor and stimulating calcium influx in cells expressing EP1 receptors (EC50 0.37 and 0.3 nM, respectively) with the rank order of activity on the other receptors comparable to the binding assays. As with binding studies, treprostinil elevated cyclic AMP with a similar high potency in cells expressing DP1, IP and EP2 receptors (EC50 0.6, 1.9 and 6.2 nM, respectively), but had low activity at the other receptors. Activation of IP, DP1 and EP2 receptors, as with treprostinil, can all result in vasodilatation of human pulmonary arteries. However, activation of EP1 receptors can provoke vasoconstriction, and hence may offset the IP-receptor mediated vasodilator effects of iloprost. Treprostinil may therefore differ from iloprost in its overall beneficial pulmonary vasorelaxant profile and other pharmacological actions, especially in diseases where the IP receptor is down-regulated.
authors.affiliation: William Harvey Research Institute, Barts and the London School of Medicine, Queen Mary University of London, Charterhouse Square, London EC1M 6BQ, UK.
authors.forename: Brendan J
authors.initials: BJ
authors.lastname: Whittle
authors.forename: Adam M
authors.initials: AM
authors.lastname: Silverstein
authors.forename: David M
authors.initials: DM
authors.lastname: Mottola
authors.forename: Lucie H
authors.initials: LH
authors.lastname: Clapp
mesh_terms: D000959:Antihypertensive Agents / Q000494:pharmacology* / Q000627:therapeutic use; D001667:Binding, Competitive; D002118:Calcium / Q000378:metabolism; D018929:Cell Culture Techniques; D000242:Cyclic AMP / Q000378:metabolism; D011464:Epoprostenol / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D057809:HEK293 Cells; D006801:Humans; D006976:Hypertension, Pulmonary / Q000188:drug therapy; D016285:Iloprost / Q000494:pharmacology* / Q000627:therapeutic use; D011869:Radioligand Assay; D044006:Receptors, Epoprostenol; D011982:Receptors, Prostaglandin / Q000819:agonists* / Q000235:genetics; D058307:Receptors, Prostaglandin E, EP2 Subtype / Q000819:agonists* / Q000235:genetics; D014162:Transfection
chemical_list: D000959:Antihypertensive Agents; C545644:PTGER2 protein, human; C113936:PTGIR protein, human; D044006:Receptors, Epoprostenol; D011982:Receptors, Prostaglandin; D058307:Receptors, Prostaglandin E, EP2 Subtype; C501562:prostanoid D receptor 1, human; D011464:Epoprostenol; D000242:Cyclic AMP; D016285:Iloprost; C427248:treprostinil; D002118:Calcium