Selectivity profiling of the novel EP2 receptor antagonist, PF-04418948, in functional bioassay systems: atypical affinity at the guinea pig EP2 receptor

Mark A Birrell, Sarah A Maher, James Buckley, Nicole Dale, Sara Bonvini, Kristof Raemdonck, Nick Pullen, Mark A Giembycz, Maria G Belvisi

Research output: Contribution to journalArticle

13 Citations (Scopus)

Abstract

BACKGROUND AND PURPOSE: Understanding the role of the EP(2) receptor has been hampered by the lack of a selective antagonist. Recently, a selective EP(2) receptor antagonist, PF-04418948, has been discovered. The aim of this study was to demonstrate the selectivity profile of PF-04418948 for the EP(2) receptor over other EP receptors using a range of isolated tissue systems.

EXPERIMENTAL APPROACH: PF-04418948 was profiled on a range of isolated tissues to assess its EP receptor potency and selectivity: ONO-DI-004-induced contraction of guinea pig trachea (EP(1)); ONO-AE1-259 and PGE(2)- induced relaxation of mouse and guinea pig trachea (EP(2)); PGE(2)-induced depolarization of guinea pig isolated vagus (EP(3)); PGE(2)-induced relaxation of human and rat trachea (EP(4)). PF-04418948 was also profiled in functional murine TP, IP, DP and FP receptor assays.

KEY RESULTS: In bioassay systems, where assessment of potency/selectivity is made against the 'native' receptor, PF-04418948 only acted as an antagonist of EP(2) receptor-mediated events. PF-04418948 competitively inhibited relaxations of murine and guinea pig trachea induced by ONO-AE1-259 and PGE(2) respectively. However, the affinity of PF-04418948 was not equal in the two preparations.

CONCLUSIONS AND IMPLICATIONS: Using a wide range of bioassay systems, we have demonstrated that PF-04418948 is a selective EP(2)-receptor antagonist. Interestingly, an atypically low affinity was found on the guinea pig trachea, questioning its utility as an EP(2) receptor assay system. Nevertheless, this compound should be an invaluable tool for investigating the biological activity of PGE(2) and the role of EP(2) receptors in health and disease.

Original languageEnglish
Pages (from-to)129-38
Number of pages10
JournalBritish Journal of Pharmacology
Volume168
Issue number1
DOIs
Publication statusPublished - Jan 2013

Fingerprint

Biological Assay
Guinea Pigs
Prostaglandins E
Trachea
Thromboxane Receptors
1-(4-fluorobenzoyl)-3-(((6-methoxy-2-naphthyl)oxy)methyl)azetidine-3-carboxylic acid
Health

Keywords

  • Animals
  • Azetidines
  • Biological Assay
  • Guinea Pigs
  • Humans
  • In Vitro Techniques
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Muscle Contraction
  • Muscle, Smooth
  • Rats
  • Rats, Sprague-Dawley
  • Receptors, Prostaglandin E, EP2 Subtype
  • Trachea
  • Journal Article
  • Research Support, Non-U.S. Gov't

Cite this

Selectivity profiling of the novel EP2 receptor antagonist, PF-04418948, in functional bioassay systems : atypical affinity at the guinea pig EP2 receptor. / Birrell, Mark A; Maher, Sarah A; Buckley, James; Dale, Nicole; Bonvini, Sara; Raemdonck, Kristof; Pullen, Nick; Giembycz, Mark A; Belvisi, Maria G.

In: British Journal of Pharmacology, Vol. 168, No. 1, 01.2013, p. 129-38.

Research output: Contribution to journalArticle

Birrell, Mark A ; Maher, Sarah A ; Buckley, James ; Dale, Nicole ; Bonvini, Sara ; Raemdonck, Kristof ; Pullen, Nick ; Giembycz, Mark A ; Belvisi, Maria G. / Selectivity profiling of the novel EP2 receptor antagonist, PF-04418948, in functional bioassay systems : atypical affinity at the guinea pig EP2 receptor. In: British Journal of Pharmacology. 2013 ; Vol. 168, No. 1. pp. 129-38.
@article{140349d434474f2da97c9153982e6e53,
title = "Selectivity profiling of the novel EP2 receptor antagonist, PF-04418948, in functional bioassay systems: atypical affinity at the guinea pig EP2 receptor",
abstract = "BACKGROUND AND PURPOSE: Understanding the role of the EP(2) receptor has been hampered by the lack of a selective antagonist. Recently, a selective EP(2) receptor antagonist, PF-04418948, has been discovered. The aim of this study was to demonstrate the selectivity profile of PF-04418948 for the EP(2) receptor over other EP receptors using a range of isolated tissue systems.EXPERIMENTAL APPROACH: PF-04418948 was profiled on a range of isolated tissues to assess its EP receptor potency and selectivity: ONO-DI-004-induced contraction of guinea pig trachea (EP(1)); ONO-AE1-259 and PGE(2)- induced relaxation of mouse and guinea pig trachea (EP(2)); PGE(2)-induced depolarization of guinea pig isolated vagus (EP(3)); PGE(2)-induced relaxation of human and rat trachea (EP(4)). PF-04418948 was also profiled in functional murine TP, IP, DP and FP receptor assays.KEY RESULTS: In bioassay systems, where assessment of potency/selectivity is made against the 'native' receptor, PF-04418948 only acted as an antagonist of EP(2) receptor-mediated events. PF-04418948 competitively inhibited relaxations of murine and guinea pig trachea induced by ONO-AE1-259 and PGE(2) respectively. However, the affinity of PF-04418948 was not equal in the two preparations.CONCLUSIONS AND IMPLICATIONS: Using a wide range of bioassay systems, we have demonstrated that PF-04418948 is a selective EP(2)-receptor antagonist. Interestingly, an atypically low affinity was found on the guinea pig trachea, questioning its utility as an EP(2) receptor assay system. Nevertheless, this compound should be an invaluable tool for investigating the biological activity of PGE(2) and the role of EP(2) receptors in health and disease.",
keywords = "Animals, Azetidines, Biological Assay, Guinea Pigs, Humans, In Vitro Techniques, Male, Mice, Mice, Inbred C57BL, Muscle Contraction, Muscle, Smooth, Rats, Rats, Sprague-Dawley, Receptors, Prostaglandin E, EP2 Subtype, Trachea, Journal Article, Research Support, Non-U.S. Gov't",
author = "Birrell, {Mark A} and Maher, {Sarah A} and James Buckley and Nicole Dale and Sara Bonvini and Kristof Raemdonck and Nick Pullen and Giembycz, {Mark A} and Belvisi, {Maria G}",
note = "{\circledC} 2012 The Authors. British Journal of Pharmacology {\circledC} 2012 The British Pharmacological Society.",
year = "2013",
month = "1",
doi = "10.1111/j.1476-5381.2012.02088.x",
language = "English",
volume = "168",
pages = "129--38",
journal = "British Journal of Pharmacology",
issn = "0007-1188",
publisher = "Wiley",
number = "1",

}

TY - JOUR

T1 - Selectivity profiling of the novel EP2 receptor antagonist, PF-04418948, in functional bioassay systems

T2 - atypical affinity at the guinea pig EP2 receptor

AU - Birrell, Mark A

AU - Maher, Sarah A

AU - Buckley, James

AU - Dale, Nicole

AU - Bonvini, Sara

AU - Raemdonck, Kristof

AU - Pullen, Nick

AU - Giembycz, Mark A

AU - Belvisi, Maria G

N1 - © 2012 The Authors. British Journal of Pharmacology © 2012 The British Pharmacological Society.

PY - 2013/1

Y1 - 2013/1

N2 - BACKGROUND AND PURPOSE: Understanding the role of the EP(2) receptor has been hampered by the lack of a selective antagonist. Recently, a selective EP(2) receptor antagonist, PF-04418948, has been discovered. The aim of this study was to demonstrate the selectivity profile of PF-04418948 for the EP(2) receptor over other EP receptors using a range of isolated tissue systems.EXPERIMENTAL APPROACH: PF-04418948 was profiled on a range of isolated tissues to assess its EP receptor potency and selectivity: ONO-DI-004-induced contraction of guinea pig trachea (EP(1)); ONO-AE1-259 and PGE(2)- induced relaxation of mouse and guinea pig trachea (EP(2)); PGE(2)-induced depolarization of guinea pig isolated vagus (EP(3)); PGE(2)-induced relaxation of human and rat trachea (EP(4)). PF-04418948 was also profiled in functional murine TP, IP, DP and FP receptor assays.KEY RESULTS: In bioassay systems, where assessment of potency/selectivity is made against the 'native' receptor, PF-04418948 only acted as an antagonist of EP(2) receptor-mediated events. PF-04418948 competitively inhibited relaxations of murine and guinea pig trachea induced by ONO-AE1-259 and PGE(2) respectively. However, the affinity of PF-04418948 was not equal in the two preparations.CONCLUSIONS AND IMPLICATIONS: Using a wide range of bioassay systems, we have demonstrated that PF-04418948 is a selective EP(2)-receptor antagonist. Interestingly, an atypically low affinity was found on the guinea pig trachea, questioning its utility as an EP(2) receptor assay system. Nevertheless, this compound should be an invaluable tool for investigating the biological activity of PGE(2) and the role of EP(2) receptors in health and disease.

AB - BACKGROUND AND PURPOSE: Understanding the role of the EP(2) receptor has been hampered by the lack of a selective antagonist. Recently, a selective EP(2) receptor antagonist, PF-04418948, has been discovered. The aim of this study was to demonstrate the selectivity profile of PF-04418948 for the EP(2) receptor over other EP receptors using a range of isolated tissue systems.EXPERIMENTAL APPROACH: PF-04418948 was profiled on a range of isolated tissues to assess its EP receptor potency and selectivity: ONO-DI-004-induced contraction of guinea pig trachea (EP(1)); ONO-AE1-259 and PGE(2)- induced relaxation of mouse and guinea pig trachea (EP(2)); PGE(2)-induced depolarization of guinea pig isolated vagus (EP(3)); PGE(2)-induced relaxation of human and rat trachea (EP(4)). PF-04418948 was also profiled in functional murine TP, IP, DP and FP receptor assays.KEY RESULTS: In bioassay systems, where assessment of potency/selectivity is made against the 'native' receptor, PF-04418948 only acted as an antagonist of EP(2) receptor-mediated events. PF-04418948 competitively inhibited relaxations of murine and guinea pig trachea induced by ONO-AE1-259 and PGE(2) respectively. However, the affinity of PF-04418948 was not equal in the two preparations.CONCLUSIONS AND IMPLICATIONS: Using a wide range of bioassay systems, we have demonstrated that PF-04418948 is a selective EP(2)-receptor antagonist. Interestingly, an atypically low affinity was found on the guinea pig trachea, questioning its utility as an EP(2) receptor assay system. Nevertheless, this compound should be an invaluable tool for investigating the biological activity of PGE(2) and the role of EP(2) receptors in health and disease.

KW - Animals

KW - Azetidines

KW - Biological Assay

KW - Guinea Pigs

KW - Humans

KW - In Vitro Techniques

KW - Male

KW - Mice

KW - Mice, Inbred C57BL

KW - Muscle Contraction

KW - Muscle, Smooth

KW - Rats

KW - Rats, Sprague-Dawley

KW - Receptors, Prostaglandin E, EP2 Subtype

KW - Trachea

KW - Journal Article

KW - Research Support, Non-U.S. Gov't

U2 - 10.1111/j.1476-5381.2012.02088.x

DO - 10.1111/j.1476-5381.2012.02088.x

M3 - Article

VL - 168

SP - 129

EP - 138

JO - British Journal of Pharmacology

JF - British Journal of Pharmacology

SN - 0007-1188

IS - 1

ER -