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