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

1989 ◽  
Vol 67 (1) ◽  
pp. 17-28 ◽  
Author(s):  
T. R. Jones ◽  
R. Zamboni ◽  
M. Belley ◽  
E. Champion ◽  
L. Charette ◽  
...  
Keyword(s):  
Guinea Pig ◽  
Receptor Antagonist ◽  
Guinea Pigs ◽  
Competitive Inhibitor ◽  
Dose Ratio ◽  
Leukotriene D4 ◽  
Small Component ◽  
Human Trachea ◽  
D4 Receptor ◽  
Orally Active

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 μM). 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 × 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 <2). L-660,711 (1.9 × 10−5 M) did not block contractions of guinea pig trachea induced by histamine, acetylcholine, 5-hydroxytryptamine, PGF2α, U-44069, or PGD2. In the presence of atropine, mepyramine, and indomethacin, L-660,711 (1.9 × 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 μg/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 μg/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.

ChemInform Abstract: Discovery of MK-0476, a Potent and Orally Active Leukotriene D4 Receptor Antagonist Devoid of Peroxisomal Enzyme Induction.

ChemInform ◽  
2010 ◽  
Vol 26 (27) ◽  
pp. no-no
Author(s):  
M. LABELLE ◽  
M. BELLEY ◽  
Y. GAREAU ◽  
J. Y. GAUTHIER ◽  
D. GUAY ◽  
...  
Keyword(s):  
Receptor Antagonist ◽  
Enzyme Induction ◽  
Leukotriene D4 ◽  
Peroxisomal Enzyme ◽  
D4 Receptor ◽  
Orally Active

The discovery of L-699,392, a novel potent and orally active leukotriene D4 receptor antagonist

1994 ◽  
Vol 4 (3) ◽  
pp. 463-468 ◽  
Author(s):  
M. Labelle ◽  
M. Belley ◽  
E. Champion ◽  
R. Gordon ◽  
K. Hoogsteen ◽  
...  
Keyword(s):  
Receptor Antagonist ◽  
Leukotriene D4 ◽  
D4 Receptor ◽  
Orally Active

Immediate hypersensitivity reactions in the guinea-pig conjunctiva: studies with a second-generation leukotriene D4 receptor antagonist, MK-571

1989 ◽  
Vol 67 (8) ◽  
pp. 845-850 ◽  
Author(s):  
Chi-Chung Chan ◽  
Francois Dagenais ◽  
Patricia Firby ◽  
Aidan Foster ◽  
Anthony W. Ford-Hutchinson
Keyword(s):  
Guinea Pig ◽  
Receptor Antagonist ◽  
Second Generation ◽  
Antigen Challenge ◽  
Hypersensitivity Reactions ◽  
Immediate Hypersensitivity ◽  
Leukotriene D4 ◽  
Permeability Changes ◽  
Therapeutic Value ◽  
D4 Receptor

The role of leukotriene D4 (LTD4) as a mediator of immediate hypersensitivity reactions in the guinea-pig conjunctiva was examined using a potent, second-generation LTD4 receptor antagonist, MK-571 (also known as L-660,711). The microvascular permeability changes in the guinea-pig conjunctiva following challenge with either LTD4 or antigen were measured through accumulation of intravenously administered 99mtechnetium-labeled albumin. Topical application of MK-571 (up to 2 h pretreatment) significantly inhibited the conjunctival responses to LTD4 (ED50 of 18–60 ng/eye) but not to histamine. The responses to a single topical antigen challenge in ovalbumin-sensitized guinea pigs were significantly inhibited (44%) by topical treatment with MK-571, in contrast to the lack of effect previously observed with prototypic antagonists. The inhibitory effects of MK-571 did not involve an action on conversion of [3H]LTC4 to LTD4 and LTE4. Following a second antigen challenge (24 h after the first), MK-571 inhibited the resultant permeability changes by 78%. Specific histamine H1 and H2 antagonists similarly inhibited the responses to the first and second challenges (63 and 74%, respectively). The present study suggests that LTD4 is involved in conjunctival hypersensitivity reactions and that potent LTD4 receptor antagonists may be of therapeutic value in the treatment of allergic conjunctivitis.Key words: allergic conjunctivitis, leukotriene D4, leukotriene D4 antagonists, MK-571, vascular permeability changes.

ChemInform Abstract: The Discovery of L-699,392, a Novel Potent and Orally Active Leukotriene D4 Receptor Antagonist.

ChemInform ◽  
2010 ◽  
Vol 25 (31) ◽  
pp. no-no
Author(s):  
M. LABELLE ◽  
M. BELLEY ◽  
E. CHAMPION ◽  
R. GORDON ◽  
K. HOOGSTEEN ◽  
...  
Keyword(s):  
Receptor Antagonist ◽  
Leukotriene D4 ◽  
D4 Receptor ◽  
Orally Active

Discovery of MK-0476, a potent and orally active leukotriene D4 receptor antagonist devoid of peroxisomal enxyme induction

1995 ◽  
Vol 5 (3) ◽  
pp. 283-288 ◽  
Author(s):  
M. Labelle ◽  
M. Belley ◽  
Y. Gareau ◽  
J.Y. Gauthier ◽  
D. Guay ◽  
...  
Keyword(s):  
Receptor Antagonist ◽  
Leukotriene D4 ◽  
D4 Receptor ◽  
Orally Active

Role of eicosanoids in hyperpnea-induced airway responses in guinea pigs

1993 ◽  
Vol 75 (6) ◽  
pp. 2797-2804 ◽  
Author(s):  
A. Garland ◽  
J. E. Jordan ◽  
D. W. Ray ◽  
S. M. Spaethe ◽  
L. Alger ◽  
...  
Keyword(s):  
Guinea Pig ◽  
Guinea Pigs ◽  
Quiet Breathing ◽  
Leukotriene D4 ◽  
Mechanically Ventilated ◽  
Respiratory System Resistance ◽  
D4 Receptor ◽  
Airway Responses ◽  
Previous Demonstration

Guinea pigs mechanically hyperventilated with dry gas exhibit hyperpnea-induced bronchoconstriction (HIB) and hyperpnea-induced bronchovascular hyperpermeability (HIBVH). Tachykinins released from airway C-fiber neurons are the central mediators of guinea pig HIB but play only a contributory role in HIBVH. Recent studies suggest that eicosanoid mediators can provoke bronchoconstriction and bronchovascular hyperpermeability, are released by dry gas hyperpnea, and can themselves elicit or modulate tachykinin release. We therefore hypothesized that eicosanoids may participate in HIB and/or HIBVH. To test these hypotheses, we analyzed respiratory system resistance changes and Evans blue-labeled albumin extravasation into the airways of 60 tracheostomized and mechanically ventilated guinea pigs. Animals were subjected to 10 min of isocapnic dry gas hyperpnea or to quiet breathing of humidified gas and received as pretreatment either piroxicam, a cyclooxygenase (CO) inhibitor; A-63162, a 5-lipoxygenase (5-LO) inhibitor; BW-755c, a combined CO and 5-LO inhibitor; ICI-198,615, a leukotriene D4 receptor antagonist; or no drug. HIB was substantially (50–80%) reduced by each of the four eicosanoid-modulating drugs. In contrast, HIBVH was reduced only by BW-755c, and this effect occurred only within the extrapulmonary airways (42% reduction). These data indicate that both CO and 5-LO products, including leukotriene D4, participate in the pathogenesis of HIB but that, like tachykinins, they play only a small contributory role in HIBVH. Together with our previous demonstration that sensory neuropeptide release is critical for the occurrence of HIB, we conclude that the roles of eicosanoids and tachykinins in guinea pig HIB are interdependent.

L-648,051, sodium 4-[3-(4-acetyl-3-hydroxy-2-propylphenoxy)-propylsulfonyl]-γ-oxo-benzenebutanoate: a leukotriene D4 receptor antagonist

1986 ◽  
Vol 64 (12) ◽  
pp. 1535-1542 ◽  
Author(s):  
T. R. Jones ◽  
Y. Guindon ◽  
R. Young ◽  
E. Champion ◽  
L. Charette ◽  
...  
Keyword(s):  
Guinea Pig ◽  
Competitive Inhibitor ◽  
Topical Agent ◽  
Guinea Pig Ileum ◽  
Leukotriene D4 ◽  
Plot Analysis ◽  
Prostaglandin F ◽  
D4 Receptor ◽  
Intraduodenal Administration

L-648,051, sodium 4-[3-(4-acetyl-3-hydroxy-2-propylphenoxy)propylsulfonyl]-γ-oxo-benzenebutanoate is a selective and competitive inhibitor of [3H]leukotriene D4 (KB value of 4.0 μM) and to a lesser extent [3H]leukotriene C4 (Ki value of 36.7 μM) 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 F2α, 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 > FPL-55712 > 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.

Treatment of interstitial cystitis with montelukast, a leukotriene D4 receptor antagonist

Urology ◽  
2001 ◽  
Vol 57 (6) ◽  
pp. 118 ◽  
Author(s):  
K Bouchelouche ◽  
J Nordling ◽  
T Hald ◽  
P Bouchelouche
Keyword(s):  
Receptor Antagonist ◽  
Interstitial Cystitis ◽  
Leukotriene D4 ◽  
D4 Receptor

A 5-HT4 agonist mosapride enhances rectorectal and rectoanal reflexes in guinea pigs

2003 ◽  
Vol 285 (2) ◽  
pp. G389-G395 ◽  
Author(s):  
Hidehiko Shimatani ◽  
Yu Kojima ◽  
Makoto Kadowaki ◽  
Tadashi Nakagawa ◽  
Hisao Fujii ◽  
...  
Keyword(s):  
Guinea Pig ◽  
Receptor Antagonist ◽  
Strain Gauge ◽  
Guinea Pigs ◽  
Internal Anal Sphincter ◽  
Pressure Transducer ◽  
Force Transducer ◽  
Rectal Distension ◽  
Pelvic Nerves ◽  
Strain Gauge Force Transducer

The rectal distension-evoked reflex rectal (R-R) contractions and internal anal sphincter (R-IAS) relaxations in guinea pigs were generated through the extrinsic sacral excitatory nerve pathway (pelvic nerves) and the intrinsic cholinergic excitatory and nitrergic inhibitory nerve pathways. The aim of the present study was to evaluate whether a prokinetic benzamide, mosapride, enhances the R-R and R-IAS reflexes mediated via 5-HT4 receptors in the guinea pig. The mechanical activities of the R and IAS were recorded with a balloon connected to a pressure transducer and a strain gauge force transducer in the anesthetized guinea pig with intact spinal-intestinal pathways. Gradual and sustained rectal distension evoked R-R contractions and synchronous R-IAS relaxations. Mosapride (0.1–1.0 mg/kg iv) dose-dependently enhanced both R-R and R-IAS reflex responses. Reflex indexes for R-R and R-IAS maximally increased from 1.0 (control) to 1.92 and 1.88, respectively. A specific 5-HT4 receptor antagonist, GR 113808 (1.0 mg/kg iv), antagonized the enhancement of the R-R and R-IAS reflexes induced by mosapride 1.0 mg/kg iv. The present results indicate that mosapride enhanced the R-R and R-IAS reflexes mediated through 5-HT4 receptors.

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