Pharmacology of the leukotriene antagonist verlukast: The (R)-enantiomer of MK-571

Abstract

Verlukast (MK-679) (3-[(3-(2-(7-chloro-2-quinolinyl)-(E)-ethenyl)phenyl)[3-(dimethylamino)- 3- oxopropyl)thio)methyl)-thio)propionic acid) is a potent and selective inhibitor of [3H]leukotriene D4 binding in guinea-pig (IC50 = 3.1 +/- 0.5 nM) and human (IC50 = 8.0 +/- 3.0 nM) lung homogenates and dimethyl sulfoxide differentiated U937 cell membrane preparations (IC50 = 10.7 +/- 1.6 nM) but is essentially inactive versus [3H]leukotriene C4 binding in guinea-pig lung homogenates (IC50 values of 19 and 33 microM). Functionally, when tested at 60 nM, it antagonized contractions of guinea-pig trachea (GPT) induced by leukotriene C4, leukotriene D4, and leukotriene E4 (respective-log KB values of 8.6, 8.8, and 8.9) and contractions of human trachea (HT) induced by leukotriene D4 (-log KB value 8.3 +/- 0.2). In contrast, verlukast (20-200 nM) failed to antagonize contractions of GPT induced by leukotriene C4 in the presence of 45 mM L-serine borate. Intravenous (i.v.) and aerosol verlukast antagonized bronchoconstriction (BC) induced in anaesthetized guinea pigs by i.v. leukotriene D4 but did not block BC to arachidonic acid or histamine. Intraduodenal verlukast (0.25 mg/kg) antagonized leukotriene D4 (0.2 micrograms/kg) induced BC in guinea pigs. Oral and aerosol administration blocked leukotriene D4-induced BC in conscious squirrel monkeys. Orally administered compound also blocked ovalbumin-induced BC in conscious sensitized rats treated with methysergide (3 micrograms/kg). The pharmacological profile for verlukast is similar to that of the racemic compound, MK-571. Verlukast is currently in clinical development for the treatment of asthma and related diseases.

Comparison of effects of dexamethasone and the leukotriene D4 receptor antagonist L-708,738 on lung function and airway cytologic findings in horses with recurrent airway obstruction

“…Indomethacin (1.4 µM) was used throughout the experiment to avoid any influence from endogenously released cyclooxygenase products. 11 After setting initial muscle tension to 1 g and an equilibration time of 30 minutes, rings were challenged once with a maximal dose of carbachol (10 µM) and washed for 1 hour in the presence of atropine (0.1 µM) and mepyramine (1 µM) to eliminate cholinergic and histaminergic influences throughout the rest of the experiment. To obtain the negative log of molar concentration of agonist producing 50% of maximal response (effective concentration 50% [EC 50 ]) measurements from a single cumulative dose response curve (DRC), bronchial tissues from 7 horses (2 to 8 rings/horse) were treated on the day of arrival with LTD 4 e in half log increments from 1 nM to 1 µM at 15-minute intervals.…”

Activity and expression of the multidrug resistance proteins P-glycoprotein, MRP1, MRP2, MRP3 and MRP5 in de novo and relapsed acute myeloid leukemia

“…To determine MRP (MRP1 and homologues MRP2 and probably MRP3) activity the compound carboxyfluorescein diacetate (CFDA) was used, which permeates the plasma membrane and upon cleavage of the ester bonds is transformed into the fluorescent anion CF. The leukotriene D4 receptor antagonist and MRP inhibitor MK-571 46 was used to inhibit CF efflux. Cells (0.5 × 10 6 ) were loaded for 20 min at 37°C, 5% CO 2 with 0.1 m CFDA or 200 ng/ml Rh123 with or without inhibitor (20 m MK-571 or 2 g/ml PSC833) in RPMI 1640 medium.…”

Induction of hyperresponsiveness in human airway tiss by neutrophils — mechanism of action

“…[37,38]. WEB 2086 [39,40], MK-679 [41] and SR 48968 [42][43][44]. These particular antagonists were chosen as neutrophiis either produce mediators that act on these receptors or produce mediators which act on the bronchial tissue causing it to release products that act on these receptors.…”