This article describes the novel pharmacological activity of MDL 28,753, a compound designed as a potential receptor antagonist of the peptidoleukotrienes. In the isolated longitudinal muscle of the guinea pig ileum, MDL 28,753 was a full agonist at the leukotriene (LT) D4 receptor and had a pD2 of 8.9 compared with a pD2 of 9.2 for LTD4. The contraction induced by MDL 28,753 was antagonized in a competitive manner by known LTD4 receptor antagonists, FPL 55,712 (pA2 = 7.3) and ICI 198615, and the peptidoleukotriene receptor antagonist, MDL 43,291 (pA2 = 6.7). However, under conditions in which the LTD4 receptors, but not the LTC4 receptors, were selectively inhibited by ICI 198615, MDL 28,753 showed no agonist activity at the LTC4 receptor. Instead, it competitively antagonized the agonist activity of LTC4 (pA2 = 6.1) in the longitudinal muscle of the guinea pig. Interestingly, under the same conditions, LTD4 also antagonized the agonist activity of LTC4. The functional difference of activity at these receptors supplies additional evidence for multiple receptors for the peptidoleukotrienes in guinea pig tissues. The unexpected lack of agonist action and unexpected antagonist activity of LTD4 at the LTC4 receptor suggests that the third carboxyl group in LTC4 is a critical binding requirement for agonist activity at the LTC4 receptor in guinea pigs.

01 Jan 1990·PharmacologyQ4 · MEDICINE

Conformationally Restricted Leukotriene Receptor Antagonists: [(Octahydro-2-oxo-7-tetradecylidene-2H-1-benzopyran-8-yl)thio]acetic Acids

Q4 · MEDICINE

Article

Author: Raddatz, Rita ; Sabol, Jeffrey S. ; Gieske, Thomas H. ; Weintraub, Philip M. ; Cregge, Robert J.

[(Octahydro-2-oxo-7-tetradecylidene-2H-1-benzopyran-8-yl)thio]acet ic acid (MDL 43,291) is a novel leukotriene (LT) receptor antagonist. It is a competitive antagonist of LTD4 (pA2 = 6.7) and LTE4 (pA2 = 6.7) and an apparent noncompetitive inhibitor of LTC4 ('pseudo' pA2 = 6.8) in the longitudinal muscle of the guinea pig ileum. At concentrations that effectively antagonize peptidoleukotriene-induced contractions, MDL 43,291 does not antagonize histamine, carbachol or substance P. In vivo, 10-30 mg/kg MDL 43,291, given intravenously, effectively inhibits increases in insufflation pressure induced by 100 ng/kg i.v. LTD4. This compound is a prototype of a novel class of leukotriene receptor antagonists that may be useful in the treatment of bronchial asthma and related disorders.

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Indication	Highest Phase	Country/Location	Organization	Date
Asthma	Discovery	US	Hoechst Marion Roussel, Inc.	-

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