Selectivity profiling of the novel EP2 receptor antagonist, PF‐04418948, in functional bioassay systems: atypical affinity at the guinea pig EP2 receptor. (18th December 2012)

• Record Type: Journal Article
• Authors: Birrell, Mark A; Maher, Sarah A; Buckley, James; Dale, Nicole; Bonvini, Sara; Raemdonck, Kristof; Pullen, Nick; Giembycz, Mark A; Belvisi, Maria G
• Is Part Of: British journal of pharmacology. Volume 168:Number 1(2013:Jan.)
• Page Start: 129
• Page End: 138
• Publication Date: 2012-12-18
• Subjects: PGE2 -- EP2 receptor -- antagonist -- functional response; Pharmacology -- Periodicals; Chemotherapy -- Periodicals; Drug Therapy -- Periodicals; Pharmacology -- Periodicals; 615.1
• DOI: 10.1111/j.1476-5381.2012.02088.x
• Languages: English
• ISSNs: 0007-1188

Abstract

Abstract : BACKGROUND AND PURPOSE: Understanding the role of the EP2 receptor has been hampered by the lack of a selective antagonist. Recently, a selective EP2 receptor antagonist, PF‐04418948, has been discovered. The aim of this study was to demonstrate the selectivity profile of PF‐04418948 for the EP2 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 (EP1 ); ONO‐AE1‐259 and PGE2 ‐ induced relaxation of mouse and guinea pig trachea (EP2 ); PGE2 ‐induced depolarization of guinea pig isolated vagus (EP3 ); PGE2 ‐induced relaxation of human and rat trachea (EP4 ). 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 EP2 receptor‐mediated events. PF‐04418948 competitively inhibited relaxations of murine and guinea pig trachea induced by ONO‐AE1‐259 and PGE2 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 EP2 ‐receptor antagonist. Interestingly, an atypically low affinity was found on the guinea pig trachea, questioning its utility as an EP2 receptor assay system. Nevertheless, this compound should be an invaluable tool for investigating the biological activity of PGE2 and the role of EP2 receptors in health and disease.