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

Abstract

Background and PurposeProstanoid 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 ApproachThe 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 ResultsPGN‐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 ImplicationsPGN‐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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“…14 Direct comparison of 0.1% doses of CP 533536-isopropyl ester and PGN 9856-isopropyl ester showed them essentially equieffective in reducing IOP at 24 h postdosing, but by 48 h, the activity of CP 533536-isopropyl ester had dissipated, whereas PGN 9856-isopropyl ester remained maximally efficacious. 11 Recently, preclinical and clinical information on a new selective EP 2 agonist prodrug, omidenepag, 15,16 have emerged. A once-daily dosing regimen was again employed 15,16 and it would appear to be a similar, but safer drug than taprenepag.…”

“…Radioligand binding studies provide no evidence for irreversible PGN 9856 binding to EP 2 receptors. 11 There are no regions of the PGN 9856 molecule that would participate in covalent binding to the EP 2 receptor protein. Nevertheless, prolonged receptor stimulation is not unprecedented and the b 2 -adrenoceptor agonists salmeterol and indacaterol exhibit atypical persistent activity.…”

“…As an important aside, the ocular tissue bioavailability of PGN 9856-isopropyl ester was compared to that of PGN 9862-isopropyl ester, a similarly potent close structural analog of PGN 9856-isopropyl ester where the O atom at position 2 is replaced by a 2, 3 double bond. 11 This double bond contributes to an a, b unsaturated ketone moiety, which may undergo Michael addition to form protein adducts. Since PGN 9862 and its ester contain such a reactive grouping, it was speculated that PGN 9862-isopropyl ester Values are meanstandard error of the mean.…”

“…25,26 Although cytokine release from HCEC-12 cells and monocytes and macrophages was examined, the proinflammatory implications of interleukin (IL)-6 and IL-8 release were not considered in the context of potential off-target DP 2 receptor activation 23 or the fact that latanoprost stimulates IL-6 and IL-8 release from human Tenon's capsule fibroblasts, but does not produce ocular inflammation. 27 PGN 9856 has no observable activity at the DP 2 receptor 11 and, therefore, is not likely to cause ocular inflammation. Prostanoid EP 2 agonists would not be expected to initiate inflammatory responses, since they exhibit broad antiinflammatory properties in neutrophils, 28 peripheral blood monocytes, 11 macrophages, 29 and lymphocytes.…”

“…27 PGN 9856 has no observable activity at the DP 2 receptor 11 and, therefore, is not likely to cause ocular inflammation. Prostanoid EP 2 agonists would not be expected to initiate inflammatory responses, since they exhibit broad antiinflammatory properties in neutrophils, 28 peripheral blood monocytes, 11 macrophages, 29 and lymphocytes. 11,[30][31][32][33] PGN 9856 potently inhibits cytokine release from lymphocytes and monocytes isolated from peripheral blood.…”