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GW627368X (( N ‐{2‐[4‐(4,9‐diethoxy‐1‐oxo‐1,3‐dihydro‐2 H ‐benzo[ f ]isoindol‐2‐yl)phenyl]acetyl} benzene sulphonamide): a novel, potent and selective prostanoid EP 4 receptor antagonist
Author(s) -
Wilson Richard J,
Giblin Gerard M P,
Roomans Susan,
Rhodes Sharron A,
Cartwright KerriAnn,
Shield Vanessa J,
Brown Jason,
Wise Alan,
Chowdhury Jannatara,
Pritchard Sara,
Coote Jim,
Noel Lloyd S,
Kenakin Terry,
BurnsKurtis Cynthia L,
Morrison Valerie,
Gray David W,
Giles Heather
Publication year - 2006
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1038/sj.bjp.0706726
Subject(s) - prostanoid , receptor , chemistry , agonist , antagonist , stereochemistry , receptor antagonist , competitive antagonist , biochemistry
1 N ‐{2‐[4‐(4,9‐diethoxy‐1‐oxo‐1,3‐dihydro‐2 H ‐benzo[ f ]isoindol‐2‐yl)phenyl]acetyl}benzene 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 (p K b ) 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 n M ) produced parallel rightward displacement of PGE 2 E /[A] curves (p K b =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 μ M ) produced 100% inhibition of U‐46619 (EC 100 )‐induced aggregation (approximate p A 2 ∼7.0). However, in rings of rabbit and piglet saphenous vein and of guinea‐pig aorta GW627368X (10 μ M ) 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 CRTH 2 , EP 2 , EP 3 , IP and FP receptors. At prostanoid EP 1 receptors, GW627368X was an antagonist with a p A 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 p A 2 of GW627368X was <5.0. 6 In competition radioligand bioassays, GW627368X had affinity for human prostanoid EP 4 and TP receptors (p K i =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 EP 4 receptor in many physiological and pathological settings.British Journal of Pharmacology (2006) 148 , 326–339. doi: 10.1038/sj.bjp.0706726