The affinity, intrinsic activity and selectivity of a structurally novel EP2 receptor agonist at human prostanoid receptors

Background and purpose: Prostanoid EP₂ 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 EP₂ receptor agonist, PGN-9856, and its therapeutic potential.

Experimental approach: The pharmacology of a series of non-prostanoid EP₂ 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 EP₂ receptors. In addition to high affinity binding, it was a potent and full EP₂ receptor agonist with a high level of selectivity at EP₁ , EP₃ , EP₄ , DP, FP, IP and TP receptors. In cells overexpressing human recombinant EP₂ receptors, PGN-9856 displayed a potency (pEC₅₀ ≥ 8.5) and a maximal response (increase in cAMP) comparable to that of the endogenous agonist PGE₂ . 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 EP₂ receptor agonist properties.

Conclusions and implications: PGN-9856 is a potent, selective and efficacious prostanoid EP₂ receptor agonist with diverse potential therapeutic applications: tocolytic, anti-inflammatory and notably anti-glaucoma.