Abstract #80215 Published in IGR 20-3

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

Coleman RA; Coleman RA; Woodrooffe AJ; Woodrooffe AJ; Clark KL; Clark KL; Toris CB; Fan S; Wang JW; Woodward DF
British Journal of Pharmacology 2019; 176: 687-698

BACKGROUND AND PURPOSE: Prostanoid EP 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 receptor agonist, PGN-9856, and its therapeutic potential. EXPERIMENTAL APPROACH: The pharmacology of a series of non-prostanoid EP 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 receptors. In addition to high affinity binding, it was a potent and full EP receptor agonist with a high level of selectivity at EP , EP , EP , DP, FP, IP and TP receptors. In cells overexpressing human recombinant EP receptors, PGN-9856 displayed a potency (pEC ≥ 8.5) and a maximal response (increase in cAMP) comparable to that of the endogenous agonist PGE . 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 receptor agonist properties. CONCLUSIONS AND IMPLICATIONS: PGN-9856 is a potent, selective and efficacious prostanoid EP receptor agonist with diverse potential therapeutic applications: tocolytic, anti-inflammatory and notably anti-glaucoma.

Asterand Bioscience, Royston, UK.

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3.8 Pharmacology (Part of: 3 Laboratory methods)
11.4 Prostaglandins (Part of: 11 Medical treatment)
3.6 Cellular biology (Part of: 3 Laboratory methods)

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