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

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.