GW627368X ((N‐{2‐[4‐(4,9‐diethoxy‐1‐oxo‐1,3‐dihydro‐2H‐benzo[f]isoindol‐2‐yl)phenyl]acetyl} benzene sulphonamide): a novel, potent and selective prostanoid EP₄ receptor antagonist

Abstract

sulphonamide (GW627368X) is a novel, potent and selective competitive antagonist of prostanoid EP 4 receptors with additional human TP receptor affinity. 2 At recombinant human prostanoid EP 4 receptors expressed in HEK293 cells, GW627368X produced parallel rightward shifts of PGE 2 concentration-effect (E/[A]) curves resulting in an affinity (pK b ) estimate of 7.970.4 and a Schild slpoe not significantly different from unity. The affinity was independent of the agonist used. 3 In rings of phenylephrine precontracted piglet saphenous vein, GW627368X (30-300 nM) produced parallel rightward displacement of PGE 2 E/[A] curves (pK b ¼ 9.270.2; slope ¼ 1). 4 GW627368X appears to bind to human prostanoid TP receptors but not the TP receptors of other species. In human washed platelets, GW627368X (10 mM) produced 100% inhibition of U-46619 (EC 100 )-induced aggregation (approximate pA 2 B7.0). However, in rings of rabbit and piglet saphenous vein and of guinea-pig aorta GW627368X (10 mM) did not displace U-46619 E/[A] curves indicating an affinity of o5.0 for rabbit and guinea-pig prostanoid TP receptors. 5 In functional assays GW627368X is devoid of both agonism and antagonist affinity for prostanoid CRTH 2 , EP 2 , EP 3 , IP and FP receptors. At prostanoid EP 1 receptors, GW627368X was an antagonist with a pA 2 of 6.0, and at prostanoid IP receptors the compound increased the maximum effect of iloprost by 55%. At rabbit prostanoid EP 2 receptors the pA 2 of GW627368X was o5.0. 6 In competition radioligand bioassays, GW627368X had affinity for human prostanoid EP 4 and TP receptors (pK i ¼ 7.070.2 (n ¼ 10) and 6.8 (n ¼ 2), respectively). Affinity for all other human prostanoid receptors was o5.3. 7 GW627368X will be a valuable tool to explore the role of the prostanoid EP 4 receptor in many physiological and pathological settings.

EP4 and EP2 Receptor Subtypes Involved in Colonic Secretion in Rat

“…A simple explanation for this discrepancy is the sensitivity of functional EP receptors of the various systems to EP receptor-related compounds. Likewise, the sensitivity to PGE 2 of the receptors in both pig vasculature and cell systems in the study by Wilson et al [22] is also two orders of magnitude higher than the sensitivity for PGE 2 at the receptors in this study; around 2-3 nM versus 200 nM.…”

“…Thus, time intervals were adjusted to the time to reach the full effect of a particular drug. To better characterize the EP 4 receptor's possible involvement in secretion, the selective EP 4 antagonist GW627368X [22] was added in a dose of 2 μ M 25 min. prior to application of PGE 2 , butaprost or OH-PGE 1 .…”

Prostaglandin E2 activates Stat3 in neonatal rat ventricular cardiomyocytes: A role in cardiac hypertrophy

“…We found that incubation of cardiomyocytes with the specific inhibitors of EP4, GW627368X and AH23848B [23,24], abolishes the PGE 2 -induced phosphorylation of nuclear Stat3 ( Fig. 2A).…”

Epoxyeicosatrienoic Acids Function as Selective, Endogenous Antagonists of Native Thromboxane Receptors: Identification of a Novel Mechanism of Vasodilation

“…Consent was obtained from each donor, and donors were de-identified. Human washed platelets were prepared as described previously (Wilson et al, 2006). Experiments were performed in the presence of the selective TP receptor antagonist SQ-29548 (1 M) and indomethacin (1 M).…”