BAY u3405, a potent and selective thromboxane A2 receptor antagonist on airway smooth muscle in vitro

• Published in: British journal of pharmacology 1991-11, Vol.104 (3), p.585-590
• Main Authors: McKenniff, M.G., Norman, P., Cuthbert, N.J., Gardiner, P.J.
• Format: Article
• Language: English
• Subjects: 11β‐PGF2; 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; Animals; BAY u3405; Biological and medical sciences; Carbazoles - pharmacology; Ferrets; Guinea Pigs; human bronchial muscle; human lung strip; Humans; In Vitro Techniques; Lung - drug effects; Lung - metabolism; Male; Medical sciences; Muscle Contraction - drug effects; Muscle, Smooth - drug effects; PGD2; PGF2α; Pharmacology. Drug treatments; Prostaglandin Endoperoxides, Synthetic - antagonists & inhibitors; Prostaglandin Endoperoxides, Synthetic - pharmacology; Prostaglandins - pharmacology; Rats; Rats, Inbred Strains; Receptors, Prostaglandin - antagonists & inhibitors; Receptors, Thromboxane; Respiratory system; Species Specificity; Stereoisomerism; Sulfonamides - pharmacology; thromboxane antagonists; Thromboxanes - antagonists & inhibitors; TXA2 receptor
• ISSN: 0007-1188; 1476-5381
• DOI: 10.1111/j.1476-5381.1991.tb12473.x

1 BAY u3405 (3(R)‐[[(4‐fluorophenyl) sulphonyl]amino]‐1,2,3,4‐tetrahydro‐9H‐carbazole‐9‐propanoic acid) has been evaluated on airway smooth muscle, from a number of species including man, for its thromboxane A2 (TXA2) antagonist activity. 2 BAY u3405 was a potent, and competitive, antagonist of the TXA2‐mimetic U46619‐induced contractions of human, guinea‐pig, rat and ferret airway smooth muscle with pA2 values between 8.0 and 8.9 and with no inherent contractile activity (10−9–10−4 m). 3 The TXA2 antagonist activity of BAY u3405 was stereoselective. Its (S)‐enantiomer, BAY u3406, was approximately 50 fold less effective against U46619 on guinea‐pig and human airway smooth muscle. 4 BAY u3405 also competitively antagonized contractions of guinea‐pig airway smooth muscle induced by prostaglandin D2 (PGD2) or its metabolite 9α, 11β‐PGF2. On human and ferret airway smooth muscle it abolished contractions induced by PGD2, PGF2α and 16, 16‐dimethyl‐PGE2. 5 A high concentration (10−6 m) of BAY u3405 had no effect on the contraction, or relaxation, of airway smooth muscle induced by a range of other agonists, nor did BAY u3405 have any effect on other prostanoid receptor types (DP, EP1, EP2, FP or IP). 6 BAY u3405, in contrast to some other TXA2 antagonists, is a potent and selective antagonist on a wide range of airways including human. This high affinity, and the oral activity of the compound described elsewhere, suggest it may be an appropriate tool to investigate the role of prostanoids in airway diseases such as asthma.