Montelukast sodium (Singulair), also known as MK-0476 (1-(((1(R)-(3-(2-(7-chloro-2-quinolinyl)-(E)-ethenyl)phenyl)(3-2-(1- hydroxy-1-methylethyl)phenyl)propyl)thio)methyl)cyclopropane) acetic acid sodium salt, is a potent and selective inhibitor of [3H]leukotriene D4 specific binding in guinea pig lung (Ki 0.18 +/- 0.03 nM), sheep lung (Ki 4 nM), and dimethylsulfoxide-differentiated U937 cell plasma membrane preparations (Ki 0.52 +/- 0.23 nM), but it was essentially inactive versus [3H]leukotriene C4 specific binding in dimethylsulfoxide-differentiated U937 cell membranes (IC50 10 microM) and [3H]leukotriene B4 specific binding in THP-1 cell membranes (IC50 40 microM). Montelukast also inhibited specific binding of [3H]leukotriene D4 to guinea pig lung in the presence of human serum albumin, human plasma, and squirrel monkey plasma with Ki values of 0.21 +/- 0.08, 0.19 +/- 0.02, and 0.26 +/- 0.02 nM, respectively. Functionally, montelukast antagonized contractions of guinea pig trachea induced by leukotriene D4 (pA2 value 9.3; slope 0.8). In contrast, montelukast (16 microM) failed to antagonize contractions of guinea pig trachea induced by leukotriene C4 (45 mM serine-borate), serotonin, acetylcholine, histamine, prostaglandin D2, or U-44069. Intravenous montelukast antagonized bronchoconstriction induced in anesthetized guinea pigs by i.v. leukotriene D4 but did not block bronchoconstriction to arachidonic acid, histamine, serotonin, or acetylcholine. Oral administration of montelukast blocked leukotriene D4 induced bronchoconstriction in conscious squirrel monkeys, ovalbumin-induced bronchoconstriction in conscious sensitized rats (ED50 0.03 +/- 0.001 mg/kg; 4 h pretreatment), and also ascaris-induced early and late phase bronchoconstriction in conscious squirrel monkeys (0.03-0.1 mg/kg; 4 h pretreatment). A continuous i.v. infusion of montelukast (8 micrograms.kg-1.min-1) resulted in a 70% decrease in the peak early response and a 75% reduction of the late response to ascaris aerosol in allergic conscious sheep. Montelukast, a potent and selective leukotriene D4 receptor antagonist with excellent in vivo activity is currently in clinical development for the treatment of asthma and related diseases.

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.

L-708,738 was bioavailable after oral administration and sustained concentrations in plasma during the dosing period that exceeded in vitro efficacy values. However, airway function did not improve, suggesting that either drug concentrations in the lungs were subtherapeutic or that cysteinyl LT may not be important mediators of airway inflammation in heaves. Results provide the first evidence of cysteinyl LT1 receptors in airways of horses.

Airway smooth muscle plasma membranes contain a variety of functional K+ channels. In particular, there is a predominance of Ca(2+)-activated K+ channels (maxi-K). Inhibition of these K+ channels has been postulated to account for the ability of charybdotoxin (ChTX) to produce contraction of airway smooth muscle and to modify the relaxant effects of beta-adrenoceptor agonists and sodium nitroprusside (SNP). Iberiotoxin (IbTX) is more selective and more potent than ChTX at blocking maxi-K channels. In this study, pharmacological experiments were performed on guinea pig trachea to determine whether IbTX produced effects similar to ChTX. The concentration-response curves to salbutamol were markedly affected by IbTX, with a > 60-fold rightward shift being produced with 20 nM IbTX. The maximal relaxation to salbutamol was reduced to 49.3 +/- 0.9, 22.3 +/- 4.7, and 15.0 +/- 2.7% of control maximum in the presence of 20, 60, and 180 nM IbTX, respectively. Similar to salbutamol, the maximal relaxation to SNP was reduced to 80 +/- 1.6, 19 +/- 1.7, and 12 +/- 2.1% of control maximum in the presence of 20, 60, and 180 nM IbTX, respectively. IbTX (180 nM) failed to produce a significant alteration of relaxation to the ATP-dependent K+ channel agonist BRL-34915. Exposure of tissues to K(+)-rich medium (80 mM) inhibited responses to salbutamol > or = SNP > isoproterenol. These results confirm and extend our earlier observations that maxi-K channels may be involved in regulating tone and relaxation of carbachol-contracted guinea pig tracheal smooth muscle. This mechanism is of particular importance for beta 2-adrenoceptor- and SNP-induced relaxation.

L-648,051, sodium 4-[3-(4-acetyl-3-hydroxy-2-propylphenoxy) propylsulfonyl]-gamma-oxo-benzenebutanoate is a selective and competitive inhibitor of [3H]leukotriene D4 (KB value of 4.0 microM) and to a lesser extent [3H]leukotriene C4 (Ki value of 36.7 microM) binding in guinea pig lung homogenates. Functionally, it selectively antagonized contractions of guinea pig trachea induced by leukotrienes C4, D4, E4, and F4 in concentrations that did not antagonize contractions induced by acetylcholine, histamine, serotonin, prostaglandin F2 alpha, or U-44069 (endoperoxide analogue). Schild plot analysis indicated that L-648,051 competitively antagonized contractions of guinea pig ileum induced by leukotriene D4 (pA2 7.7) and contractions of trachea induced by leukotrienes D4, E4, and F4 (pA2 7.3, 7.4, and 7.5, respectively). Contractions of guinea pig trachea induced by leukotriene C4 were inhibited in a noncompetitive fashion (Schild plot slope, 0.45). Developed contractions of trachea induced by the leukotrienes were rapidly reversed by L-648,051 greater than FPL-55712 greater than L-649,923. Intravenous L-648,051 selectively blocked bronchoconstriction induced in anaesthetized guinea pigs by intravenous leukotrienes C4, D4, and E4 but not that induced by arachidonic acid, serotonin, U-44069, or acetylcholine. The compound displayed poor activity following intraduodenal administration. The profile of activity for L-648,051 indicates that it may be a useful topical agent for studying the role of leukotrienes in diseases such as bronchial asthma.