Binding and activity of the prostacyclin receptor (IP) agonists, treprostinil and iloprost, at human prostanoid receptors: Treprostinil is a potent DP₁ and EP₂ agonist
2012
Whittle, Brendan J. | Silverstein, Adam M. | Mottola, David M. | Clapp, Lucie H.
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 3.9nM, 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 32nM, 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 0.3nM, 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 6.2nM, 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.
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