Pharmacological profile of CR3465, a new leukotriene CysLT1 receptor antagonist with broad anti-inflammatory activity

Background and purpose:The objective of this study was to characterize the effects of the cysteinyl leukotriene receptor antagonist, montelukast (0.1-2 mmol·L ).Experimental approach: Generation of reactive oxygen species was measured by lucigenin-and luminol-enhanced chemiluminescence, elastase release by a colourimetric assay, leukotriene B4 and cAMP by competitive binding ELISA procedures, and Ca 2+ fluxes by fura-2/AM-based spectrofluorimetric and radiometric ( 45 Ca 2+ ) procedures. Key results: Pre-incubation of neutrophils with montelukast resulted in dose-related inhibition of the generation of reactive oxygen species and leukotriene B4 by chemoattractant-activated neutrophils, as well as release of elastase, all of which were maximal at 2 mmol·L -1 (mean percentages of the control values of 30 Ϯ 1, 12 Ϯ 3 and 21 Ϯ 3 respectively; P < 0.05). From a mechanistic perspective, treatment of chemoattractant-activated neutrophils with montelukast resulted in significant reductions in both post-peak cytosolic Ca 2+ concentrations and store-operated Ca 2+ influx. These montelukast-mediated alterations in Ca 2+ handling by the cells were associated with a significant elevation in basal cAMP levels, which resulted from inhibition of cyclic nucleotide phosphodiesterases. Conclusions and implications: Montelukast, primarily a cysteinyl leukotriene (CysLT1) receptor antagonist, exhibited previously undocumented, secondary, neutrophil-directed anti-inflammatory properties, which appeared to be cAMP-dependent.

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“…, 1987). More recently, CR3465, a novel CysLT 1 receptor antagonist, was reported to possess PDE inhibitory activity (Ferrari et al. , 2004).…”

Section: Discussionmentioning

confidence: 99%

“…, 1984; Hay et al. , 1987), whereas for CR3465 the combination of CysLT 1 receptor antagonism and PDE inhibitory activity was considered to be beneficial, because the latter property conferred additional protection by targeting spasmogenic and inflammatory mediators other than CysLTs (Ferrari et al. , 2004).…”

Section: Discussionmentioning

confidence: 99%

Montelukast inhibits neutrophil pro‐inflammatory activity by a cyclic AMP‐dependent mechanism

Anderson

Theron

Gravett

et al. 2008

British J Pharmacology

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“…Secondary, nonspecific PDE inhibitory activity has also been described for other CysLT 1 R antagonists, including several of the early, experimental CysLT 1 R antagonists, such as FPL55712 and LY171883 [43,44]. More recently, CR3465, a novel CysLT 1 R antagonist, was reported to possess nonspecific PDE inhibitory activity [45]. In the case of FPL55712 and LY171883, PDE inhibitory activity appeared to represent a limitation in respect of specificity of pharmacological mode of action [43,44].…”

Section: Other Agents That Combine Antagonism Of Cysltrs and Nonspecimentioning

confidence: 93%

“…In the case of FPL55712 and LY171883, PDE inhibitory activity appeared to represent a limitation in respect of specificity of pharmacological mode of action [43,44]. In the case of CR3465, however, the combination of CysLT 1 R antagonism and PDE inhibitory activity was considered to be beneficial because the latter property may confer additional protection by targeting spasmogenic and inflammatory mediators other than CysLTs [45]. From a molecular structure/function perspective, montelukast and CR3465 both possess a quinoline moiety, which may underpin the PDE inhibitory activities of these agents [45,46].…”

Section: Other Agents That Combine Antagonism Of Cysltrs and Nonspecimentioning

confidence: 99%

Montelukast: More than a Cysteinyl Leukotriene Receptor Antagonist?

Tintinger

Feldman

Theron

et al. 2010

The Scientific World JOURNAL

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The prototype cysteinyl leukotriene receptor antagonist, montelukast, is generally considered to have a niche application in the therapy of exercise- and aspirin-induced asthma. It is also used as add-on therapy in patients whose asthma is poorly controlled with inhaled corticosteroid monotherapy, or with the combination of a long-acting β(2)-agonist and an inhaled corticosteroid. Recently, however, montelukast has been reported to possess secondary anti-inflammatory properties, apparently unrelated to conventional antagonism of cysteinyl leukotriene receptors. These novel activities enable montelukast to target eosinophils, monocytes, and, in particular, the corticosteroid-insensitive neutrophil, suggesting that this agent may have a broader spectrum of anti-inflammatory activities than originally thought. If so, montelukast is potentially useful in the chemotherapy of intermittent asthma, chronic obstructive pulmonary disease, cystic fibrosis, and viral bronchiolitis, which, to a large extent, involve airway epithelial cell/neutrophil interactions. The primary objective of this mini-review is to present evidence for the cysteinyl leukotrien–independent mechanisms of action of montelukast and their potential clinical relevance.

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“…A recent study examining the effect of mon- telukast on THP-1 cells revealed that montelukast inhibited NF-B activation in THP-1 cells in a dose-dependent manner (47). Furthermore, montelukast significantly inhibited lipopolysaccharide-induced IL-6 (60), TNF-␣ (20), and MCP-1 production (47) in the peripheral blood mononuclear cells of controls and patients with asthma. However, these effects of montelukast were observed at higher doses and more studies are required to determine a lower therapeutic dose.…”

Section: Redox Signaling In Lungs 685mentioning

confidence: 96%

Current Concepts of Redox Signaling in the Lungs

Rahman

Yang

Biswas

2006

Antioxidants & Redox Signaling

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In the intracellular redox state (GSH/GSSG) the cell plays a key role in the regulation and potentiation of the inflammatory response in lung cells. Glutathione and thioredoxin are the important protective antioxidants in the lungs. Regulation of intracellular redox glutathione and thioredoxin levels in response to reactive oxygen/nitrogen species and in inflammation should have critical effects on different lung cells on the activation of redox sensor/signal transduction pathways and various transcription factors. Possibly via the modification of cysteine residues, oxidative stress activates multiple stress kinase pathways and transcription factors nuclear factor-kappaB and activator protein-1, which differentially regulate the genes for proinflammatory cytokines as well as the protective antioxidant genes. Emerging data suggest that protein-S-thiolation, protein-S-nitrosation, and oxidation of protein-SH (formation of sulfenic, sulfinic, and sulfonic acids) are critical in redox signaling during normal physiology and under oxidative stress in controlling the cellular processes. In this review, we discuss the recent findings in the context of redox signaling during inflammation, pathology, and the role of redox modulating agents/dietary interventions either to inhibit abnormal signaling or induce/boost the endogenous antioxidant systems. Furthermore, this also provides information as to how antioxidants are involved in redox signaling to control inflammatory and oxidative stress in the lung.

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Pharmacological profile of CR3465, a new leukotriene CysLT1 receptor antagonist with broad anti-inflammatory activity

Cited by 7 publications

References 32 publications

Montelukast inhibits neutrophil pro‐inflammatory activity by a cyclic AMP‐dependent mechanism

Montelukast inhibits neutrophil pro‐inflammatory activity by a cyclic AMP‐dependent mechanism

Montelukast: More than a Cysteinyl Leukotriene Receptor Antagonist?

Current Concepts of Redox Signaling in the Lungs

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