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BAY u3405, a potent and selective thromboxane A 2 receptor antagonist on airway smooth muscle in vitro
Author(s) -
McKenniff M.G.,
Norman P.,
Cuthbert N.J.,
Gardiner P.J.
Publication year - 1991
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 - 10.1111/j.1476-5381.1991.tb12473.x
Subject(s) - thromboxane a2 , antagonist , in vitro , bay , chemistry , thromboxane receptor , pharmacology , receptor , biology , medicine , anatomy , biochemistry , oceanography , geology
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 A 2 (TXA 2 ) antagonist activity. 2 BAY u3405 was a potent, and competitive, antagonist of the TXA 2 ‐mimetic U46619‐induced contractions of human, guinea‐pig, rat and ferret airway smooth muscle with pA 2 values between 8.0 and 8.9 and with no inherent contractile activity (10 −9 –10 −4 m ). 3 The TXA 2 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 D 2 (PGD 2 ) or its metabolite 9α, 11β‐PGF 2 . On human and ferret airway smooth muscle it abolished contractions induced by PGD 2 , PGF 2α and 16, 16‐dimethyl‐PGE 2 . 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, EP 1 , EP 2 , FP or IP). 6 BAY u3405, in contrast to some other TXA 2 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.