A novel leukotriene D4/E4 antagonist, SR2640 (2-[3-(2-quinolylmethoxy)phenylamino]benzoic acid).
We have studied the leukotriene antagonistic activity of a novel compound, SR2640 (2-[3-(2-quinolylmethoxy)phenylamino]benzoic acid), in vitro and in vivo. SR2640 inhibited LTD4- but not histamine-induced contractions of guinea-pig ileum and trachea in a concentration-dependent manner. Schild plot analysis of tracheal LTD4 antagonism yielded a pA2 value of 8.7 and a slope not different from unity. SR2640 concentration dependently inhibited the binding of 0.4 nM [3H]LTD4 to guinea-pig lung membranes with an IC50 value of 23 nM. The curve was parallel to that of unlabelled LTD4 (IC50 = 2.2 nM). SR2640 was equally effective in antagonizing LTD4 and LTE4, but was much less potent in reducing LTC4-induced ileum contractions. In vivo, SR2640 in the dose range 0.03-1.00 mg/kg shifted the dose-response curve for guinea-pig bronchoconstriction induced by intravenous LTD4 administration to the right at a rate proportional to the dose of SR2640, without reducing the maximum attainable obstruction: the slope of the Schild plot was 0.99. SR2640 (1 mg/kg) also caused a significant inhibition of antigen-induced bronchoconstriction in anaesthetized guinea-pigs pretreated with pyrilamine, indomethacin, propranolol and suxamethonium. In conclusion, SR2640 appears to be a potent and selective competitive LTD4/LTE4 antagonist, and may be useful in elucidating the role of leukotrienes in human asthma.
Ahnfelt-Rønne
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I
Department of Pharmacology, Leo Pharmaceutical Products, Ballerup, Denmark.
Kirstein
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D
Kaergaard-Nielsen
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C
D000818:Animals; D016718:Arachidonic Acid; D001095:Arachidonic Acids / Q000378:metabolism; D001980:Bronchi / Q000187:drug effects; D005260:Female; D006168:Guinea Pigs; D066298:In Vitro Techniques; D007962:Leukocytes / Q000187:drug effects / Q000378:metabolism; D017999:Leukotriene E4; D008168:Lung / Q000187:drug effects / Q000378:metabolism; D008297:Male; D008566:Membranes / Q000187:drug effects / Q000378:metabolism; D009130:Muscle, Smooth / Q000187:drug effects; D011804:Quinolines / Q000494:pharmacology*; D051381:Rats; D011919:Rats, Inbred Strains; D013189:SRS-A / Q000031:analogs & derivatives* / Q000037:antagonists & inhibitors*; D013566:Sympathomimetics / Q000494:pharmacology; D014132:Trachea / Q000187:drug effects
D001095:Arachidonic Acids; D011804:Quinolines; D013189:SRS-A; D013566:Sympathomimetics; C059177:SR 2640; D016718:Arachidonic Acid; D017999:Leukotriene E4