The affinity, intrinsic activity and selectivity of a structurally novel EP 2 receptor agonist at human prostanoid receptors

R. A. Coleman, A. J. Woodrooffe, K. L. Clark, Carol B Toris, Shan Fan, J. W. Wang, D. F. Woodward

Research output: Contribution to journalArticle

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Abstract

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.

Original languageEnglish (US)
Pages (from-to)687-698
Number of pages12
JournalBritish Journal of Pharmacology
Volume176
Issue number5
DOIs
StatePublished - Mar 2019

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Tocolytic Agents
Prostaglandins
Anti-Inflammatory Agents
Ocular Hypotension
Thromboxane Receptors
Tocolysis
Prostaglandins E
Ion Channels
Glaucoma
Primates
Therapeutics
Pharmacology
Ligands
Enzymes
Proteins
prostaglandin F2alpha receptor

ASJC Scopus subject areas

  • Pharmacology

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The affinity, intrinsic activity and selectivity of a structurally novel EP 2 receptor agonist at human prostanoid receptors . / Coleman, R. A.; Woodrooffe, A. J.; Clark, K. L.; Toris, Carol B; Fan, Shan; Wang, J. W.; Woodward, D. F.

In: British Journal of Pharmacology, Vol. 176, No. 5, 03.2019, p. 687-698.

Research output: Contribution to journalArticle

Coleman, R. A. ; Woodrooffe, A. J. ; Clark, K. L. ; Toris, Carol B ; Fan, Shan ; Wang, J. W. ; Woodward, D. F. / The affinity, intrinsic activity and selectivity of a structurally novel EP 2 receptor agonist at human prostanoid receptors In: British Journal of Pharmacology. 2019 ; Vol. 176, No. 5. pp. 687-698.
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AB - 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.

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