A novel leukotriene D4/E4 antagonist, SR2640 (2-[3-(2-quinolylmethoxy)phenylamino]benzoic acid).

Abstract

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.

• Authors: I Ahnfelt-Rønne, D Kirstein, C Kaergaard-Nielsen
• Journal: European journal of pharmacology (Eur J Pharmacol) Vol. 155 Issue 1-2 Pg. 117-28 (Oct 11 1988) ISSN: 0014-2999 [Print] Netherlands
• PMID: 2854067 (Publication Type: Journal Article)

Chemical References

• Arachidonic Acids
• Quinolines
• SRS-A
• Sympathomimetics
• SR 2640
• Arachidonic Acid
• Leukotriene E4

Topics

• Animals
• Arachidonic Acid
• Arachidonic Acids (metabolism)
• Bronchi (drug effects)
• Female
• Guinea Pigs
• In Vitro Techniques
• Leukocytes (drug effects, metabolism)
• Leukotriene E4
• Lung (drug effects, metabolism)
• Male
• Membranes (drug effects, metabolism)
• Muscle, Smooth (drug effects)
• Quinolines (pharmacology)
• Rats
• Rats, Inbred Strains
• SRS-A (analogs & derivatives, antagonists & inhibitors)
• Sympathomimetics (pharmacology)
• Trachea (drug effects)