• GW627368X;
  • EP4;
  • prostanoid;
  • receptor;
  • competitive;
  • antagonist
  • 1
    N-{2-[4-(4,9-diethoxy-1-oxo-1,3-dihydro-2H-benzo[f]isoindol-2-yl)phenyl]acetyl}benzene sulphonamide (GW627368X) is a novel, potent and selective competitive antagonist of prostanoid EP4 receptors with additional human TP receptor affinity.
  • 2
    At recombinant human prostanoid EP4 receptors expressed in HEK293 cells, GW627368X produced parallel rightward shifts of PGE2 concentration–effect (E/[A]) curves resulting in an affinity (pKb) estimate of 7.9±0.4 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 PGE2E/[A] curves (pKb=9.2±0.2; slope=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 μM) produced 100% inhibition of U-46619 (EC100)-induced aggregation (approximate pA2 ∼7.0). However, in rings of rabbit and piglet saphenous vein and of guinea-pig aorta GW627368X (10 μM) did not displace U-46619 E/[A] curves indicating an affinity of <5.0 for rabbit and guinea-pig prostanoid TP receptors.
  • 5
    In functional assays GW627368X is devoid of both agonism and antagonist affinity for prostanoid CRTH2, EP2, EP3, IP and FP receptors. At prostanoid EP1 receptors, GW627368X was an antagonist with a pA2 of 6.0, and at prostanoid IP receptors the compound increased the maximum effect of iloprost by 55%. At rabbit prostanoid EP2 receptors the pA2 of GW627368X was <5.0.
  • 6
    In competition radioligand bioassays, GW627368X had affinity for human prostanoid EP4 and TP receptors (pKi=7.0±0.2 (n=10) and 6.8 (n=2), respectively). Affinity for all other human prostanoid receptors was <5.3.
  • 7
    GW627368X will be a valuable tool to explore the role of the prostanoid EP4 receptor in many physiological and pathological settings.

British Journal of Pharmacology (2006) 148, 326–339. doi:10.1038/sj.bjp.0706726