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. 2019 Mar;176(5):687-698.
doi: 10.1111/bph.14525. Epub 2019 Jan 4.

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

R A Coleman  1 , A J Woodrooffe  1 , K L Clark  1 , C B Toris  2 , S Fan  2 , J W Wang  3 , D F Woodward  3
Affiliations

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

R A Coleman et al. Br J Pharmacol. 2019 Mar.

Abstract

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.

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Figures

Figure 1
Figure 1
Structures of compounds used in these experiments: PGN‐9856, PGN‐9858, PGN‐9862 and PGN‐9863.
Figure 2
Figure 2
Concentration‐dependent displacement of the binding of radiolabelled PGE2 to human recombinant EP2 receptors by PGN‐9856. Data are shown as mean ± SEM for n = 3–4 experiments.
Figure 3
Figure 3
Agonist potency (cAMP response) of PGN‐9856, PGN‐9858, PGN ‐9862, PGN‐9863 and PGE2 at human recombinant EP2 receptors. Data are expressed relative to the response to 3 x 10‐8M PGE2 (set at 100%). Values shown are means ± SEM from 3 individual experiments.
Figure 4
Figure 4
(A) Effect of PGN‐9856, PGN‐9858, PGN‐9862, PGN‐9863 and the standard EP2 receptor agonist, butaprost, on TNF‐α release from human LPS‐stimulated peripheral blood monocytes Data are mean ± SEM from 4–5 individual experiments. (B) Activity of PGN‐9856, PGN‐9858, PGN‐9862, PGN‐9863 and the standard EP2 receptor agonist, butaprost, on IL‐2 release from in human lymphocytes stimulated by anti‐CD3 antibody. Data are mean ± SEM from 3–4 individual experiments.
Figure 5
Figure 5
Comparison of the effects of PGN‐9856 and butaprost on inhibition of TNF‐α release in LPS‐stimulated whole blood. Basal release (no LPS) is indicated. Data are given as mean ± SEM from four donors.
Figure 6
Figure 6
(A) Inhibitory effects of PGN‐9856 (n = 3) and the standard EP2 receptor agonist butaprost (n = 7) and DMSO vehicle control (n = 7) on electrically stimulated human isolated non‐pregnant myometrium. Data shown are mean ± SEM % of the inhibition induced by sodium nitroprusside (SNP) 10‐4M. (B) Original recordings of responses of human myometrial smooth muscle to electrical stimulation at 5 Hz for 10 sec every 100 sec and the inhibition of these responses produced by increasing cumulative concentrations of butaprost (upper trace) and PGN9856 (lower trace). Dots indicate approximately when drug concentrations were administered in 0.5 log unit increments at approximately 10 min intervals, beginning with 10‐9 M (‐9). Vertical bar indicates calibration of tension developed (g) for both traces.
Figure 7
Figure 7
Comparison of the effects of PGN‐9856‐isopropyl ester (PGN‐9856i) and PF‐04217329 on the intraocular pressure of laser‐induced ocular hypertensive monkeys. PGN‐9856i produced a significant reduction in intraocular pressure at the 6, 24, and 48 h post‐dosing time points, compared to the immediate pre‐dosing time point (time 0). PF‐04217329 also produced identically significant reductions in IOP at all time points except at 48 h, when the effect on intraocular pressure had essentially returned to baseline and no statistically significant effect was apparent. Data are means ± SEM, n = 6.
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