Exploring the Mechanism and Impact of GW627368X: A Selective EP4 Receptor Antagonist

GW627368X is a newly discovered compound that acts as a strong and specific blocker of the prostanoid EP4 receptors, showing a high level of selectivity. It also has the ability to bind to human TP receptors. In experiments with human EP4 receptors expressed in HEK293 cells, GW627368X demonstrated competitive antagonism, with an estimated affinity of 7.9±0.4 and a Schild slope close to unity, indicating its selectivity. The compound was also tested on piglet saphenous veins, where it showed a similar effect with an affinity of 9.2±0.2.

GW627368X was found to selectively bind to human TP receptors, not affecting those from other species. In human platelets, it was able to completely inhibit aggregation induced by U-46619, suggesting a high potency. However, it did not show significant binding to TP receptors from rabbits and guinea pigs.

In functional assays, GW627368X lacked agonist activity and antagonist affinity for several prostanoid receptors, including CRTH2, EP2, EP3, IP, and FP. It did act as an antagonist at EP1 receptors with a pA2 of 6.0 and showed an increase in the maximum effect of iloprost at IP receptors. At EP2 receptors in rabbits, its pA2 was less than 5.0.

In radioligand binding assays, GW627368X showed measurable affinity for human EP4 and TP receptors, with pKi values of 7.0±0.2 and 6.8, respectively. It had low affinity for other prostanoid receptors, all below 5.3.

The study concludes that GW627368X is a promising compound for investigating the role of the prostanoid EP4 receptor in various physiological and pathological conditions. The research was published in the British Journal of Pharmacology in 2006, volume 148, pages 326–339.