The affinity, intrinsic activity and selectivity of a structurally novel EP ₂ receptor agonist at human prostanoid receptors

Background and Purpose: Prostanoid EP ₂ receptor agonists exhibit several activities including ocular hypotension, tocolysis and anti-inflammatory activity. This report describes the affinity and selectivity of a structurally novel, non-prostanoid EP ₂ receptor agonist, PGN-9856, and its therapeutic potential. Experimental Approach: The pharmacology of a series of non-prostanoid EP ₂ receptor agonists was determined according to functional and radioligand binding studies, mostly using human recombinant prostanoid receptor transfectants. The selectivity of PGN-9856, as the preferred compound, was subsequently determined by using a diverse variety of non-prostanoid target proteins. The therapeutic potential of PGN-9856 was addressed by determining its activity in relevant primate cell, tissue and disease models. Key Results: PGN-9856 was a selective and high affinity (pKi ≥ 8.3) ligand at human recombinant EP ₂ receptors. In addition to high affinity binding, it was a potent and full EP ₂ receptor agonist with a high level of selectivity at EP ₁ , EP ₃ , EP ₄ , DP, FP, IP and TP receptors. In cells overexpressing human recombinant EP ₂ receptors, PGN-9856 displayed a potency (pEC ₅₀ ≥ 8.5) and a maximal response (increase in cAMP) comparable to that of the endogenous agonist PGE ₂ . PGN-9856 exhibited no appreciable affinity (up 10 μM) for a range of 53 other receptors, ion channels and enzymes. Finally, PGN-9856 exhibited tocolytic, anti-inflammatory and long-acting ocular hypotensive properties consistent with its potent EP ₂ receptor agonist properties. Conclusions and Implications: PGN-9856 is a potent, selective and efficacious prostanoid EP ₂ receptor agonist with diverse potential therapeutic applications: tocolytic, anti-inflammatory and notably anti-glaucoma.