Pharmacology of L-660,711 (MK-571): a novel potent and selective leukotriene D₄ receptor antagonist

Abstract

L-660,711 (3-(3-(2-(7-chloro-2-quinolinyl)ethenyl)phenyl) ((3-dimethyl amino-3-oxo propyl)thio)methyl)thio)propanoic acid is a potent and selective competitive inhibitor of [3H]leukotriene D4 binding in guinea pig (Ki value, 0.22 nM) and human (Ki value, 2.1 nM) lung membranes but is essentially inactive versus [3H]leukotriene C4 binding (IC50 value in guinea pig lung, 23 microM). Functionally it competitively antagonized contractions of guinea pig trachea and ileum induced by leukotriene (LT) D4 (respective pA2 values, 9.4 and 10.5) and LTE4 (respective pA2 values, 9.1 and 10.4) and contractions of human trachea induced by LTD4 (pA2 value, 8.5). L-660,711 (5.8 x 10(-8)M) antagonized contractions of guinea pig trachea induced by LTC4 in the absence (dose ratio = 28) but not in the presence of 45 mM L-serine borate (dose ratio less than 2). L-660,711 (1.9 x 10(-5)M) did not block contractions of guinea pig trachea induced by histamine, acetylcholine, 5-hydroxytryptamine, PGF2 alpha, U-44069, or PGD2. In the presence of atropine, mepyramine, and indomethacin, L-660,711 (1.9 x 10(-5)M) inhibited a small component of the response to antigen on guinea pig trachea but completely blocked anti-IgE-induced contractions of human trachea. L-660,711 (i.v.) antagonized bronchoconstriction induced in anesthetized guinea pigs by i.v. LTC4, LTD4, and LTE4 but did not block bronchoconstriction to arachidonic acid, U-44069, 5-hydroxytryptamine, histamine, or acetylcholine. Intraduodenal L-660,711 antagonized LTD4 (0.2-12.8 micrograms/kg)-induced bronchoconstriction in guinea pigs, and p.o. L-660,711 blocked LTD4- and Ascaris-induced bronchoconstriction in conscious squirrel monkeys and ovalbumin-induced bronchoconstriction in conscious sensitized rats treated with methysergide (3 micrograms/kg). The pharmacological profile of L-660,711 indicates that it is a potent, selective, orally active leukotriene receptor antagonist which is well suited to determine the role played by LTD4 and LTE4 in asthma and other pathophysiologic conditions.

The Type 1 Cysteinyl Leukotriene Receptor Triggers Calcium Influx and Chemotaxis in Mouse αβ- and γδ Effector T Cells

“…The Ca 2ϩ mobilization observed in LatY136F CD4 ϩ T cells was dose dependent and was inhibited by MK571 (Fig. 2C), a specific pharmacological inhibitor of CysLT 1 (18). In conclusion, the effector CD4 ϩ T cells found in LatY136F mice that expressed high levels of CysLT 1 mobilized intracellular Ca 2ϩ in response to the CysLT 1 ligand LTD 4 .…”

Cysteinyl Leukotriene Receptor 1/2 Antagonists Nonselectively Modulate Organic Anion Transport by Multidrug Resistance Proteins (MRP1-4)

“…This interest extended to other MRPs as their roles in drug distribution and elimination have been elucidated. MK-571 was originally developed as a CysLT receptor (CysLTR) antagonist to treat asthma (Jones et al, 1989). However, it also sensitizes tumor cells expressing MRP1, and inhibits MRP1-mediated transport of organic anions including LTC 4 (Gekeler et al, 1995;Cole, 2014a).…”

CysLT1 leukotriene receptor antagonists inhibit the effects of nucleotides acting at P2Y receptors

“…The CysLT receptor nomenclature was originally based on the sensitivity to the antagonists, which include montelukast, zafirlukast, pranlukast, pobilukast and MK571 [9]. Montelukast (Singulair ® ), a potent CysLT 1 receptor antagonist belonging to the chemical class of quinolines [18], is an effective and well-tolerated preventative drug for asthma and allergic rhinitis in adults and children [19]. Pranlukast (Onon ® , Azlaire ® ) belongs to the chemical class of benzopyrans [20] and is indicated for the prophylactic treatment of chronic bronchial asthma in pediatric and adult patients and is currently on the market only in Japan and South America [21].…”