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.