Indole-3-acetic Acid Antagonists of the Prostaglandin D<sub>2</sub> Receptor CRTH2

Armer, Richard; Ashton, Mark; Boyd, E. Andrew; Brennan, Chris J; Brookfield, Frederick A.; Gazi, Lucien; Gyles, Shân L.; Hay, Philip A.; Hunter, Michael; Middlemiss, D.; Whittaker, Mark; Xue, Luzheng; Pettipher, Roy

doi:10.1021/jm050519b

Cited by 47 publications

(31 citation statements)

References 20 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…We observed that PGD 2 can induce MUC5B protein in a dose-dependent manner in both cells (Figs. 3, D (33,34), or the CRTH2/DP2 antagonist, OC0459 (35). PGD 2 -dependent MUC5B gene expression in NCI-H292 cells was significantly inhibited by S5751 in a dose-dependent manner, whereas OC0459 had very little effect (Fig.…”

Section: Pgd 2 Induces Muc5b Expression In Both Nhne Cells and Human mentioning

confidence: 91%

The Extracellular Signal-regulated Kinase Mitogen-activated Protein Kinase/Ribosomal S6 Protein Kinase 1 Cascade Phosphorylates cAMP Response Element-binding Protein to Induce MUC5B Gene Expression via d-Prostanoid Receptor Signaling

Choi

Lee

Aoyagi

et al. 2011

Journal of Biological Chemistry

View full text Add to dashboard Cite

Mucus hypersecretion is a prominent feature of respiratory diseases, and MUC5B is a major airway mucin. Mucin gene expression can be affected by inflammatory mediators, including prostaglandin (PG) D 2, an inflammatory mediator synthesized by hematopoietic PGD synthase (H-PGDS). PGD 2 binds to either D-prostanoid receptor (DP1) or chemoattractant receptor homologous molecule expressed on T-helper type 2 cells (CRTH2). We investigated the mechanisms by which PGD 2 induces MUC5B gene expression in airway epithelial cells. Western blot analysis showed that H-PGDS was highly expressed in nasal polyps. Similar results were obtained for PGD 2 expression. In addition, we could clearly detect the expressions of both H-PGDS and DP1 in nasal epithelial cells but not CRTH2. We demonstrated that PGD 2 increased MUC5B gene expression in normal human nasal epithelial cells as well as in NCI-H292 cells in vitro. S5751, a DP1 antagonist, inhibited PGD 2 -induced MUC5B expression, whereas a CRTH2 antagonist (OC0459) did not. These data suggest that PGD 2 induced MUC5B expression via DP1. Pretreatment with extracellular signal-regulated kinase (ERK) inhibitor (PD98059) blocked both PGD 2 -induced ERK mitogen-activated protein kinase (MAPK) activation and MUC5B expression. Proximity ligation assays showed direct interaction between RSK1 and cAMP response element-binding protein (CREB). Stimulation with PGD 2 caused an increase in intracellular cAMP levels, whereas intracellular Ca 2؉ did not have such an effect. PGD 2 -induced MUC5B mRNA levels were regulated by CREB via direct interaction with two cAMP-response element sites (؊921/؊914 and ؊900/؊893). Finally, we demonstrated that PGD 2 can induce MUC5B overproduction via ERK MAPK/ RSK1/CREB signaling and that DP1 receptor may have suppressive effects in controlling MUC5B overproduction in the airway.Mucus secretion in the airway, including the nasal and paranasal sinus cavities, is drained by the mucociliary transport system (1). Normal mucus secretion is essential for survival (2), but upregulation of mucin gene expression is a major manifestation of chronic airway diseases such as allergic rhinitis, asthma, and cystic fibrosis (3, 4). Patients suffering from these diseases have pathological abnormalities in both the submucosal glands and surface epithelium, characterized by inflammation, increased mucus cell number, and increased airway mucus. Several classes of inflammatory mediators have been implicated in the process of mucus hypersecretion based on their ability to stimulate secretion from cultured cells and tissue explants (5). These inflammatory mediators are lipopolysaccharides (6), reactive oxygen species (7), and arachidonic acid metabolites (8, 9).A total of 20 different mucin genes have been identified and subdivided into two groups, membrane-bound and secreted mucins, according to Human Genome Mapping conventions. The secreted mucins are MUC5AC, MUC5B, MUC6, and MUC19 (10 -13). Mucins are primarily synthesized by two different cell types in the airway tract, namely...

show abstract

Section: Pgd 2 Induces Muc5b Expression In Both Nhne Cells and Human mentioning

confidence: 91%

The Extracellular Signal-regulated Kinase Mitogen-activated Protein Kinase/Ribosomal S6 Protein Kinase 1 Cascade Phosphorylates cAMP Response Element-binding Protein to Induce MUC5B Gene Expression via d-Prostanoid Receptor Signaling

Choi

Lee

Aoyagi

et al. 2011

Journal of Biological Chemistry

View full text Add to dashboard Cite

show abstract

“…Among these compounds are the inhibitors of transthyretin amyloid formation [102], the fenamates (flufenamic acid 94 and niflumic acid 95) and diflunisal 96. A novel series of the potent NSAIDs, the fluoroindolecarboxylic acids (sulindac sulfide 97, L-88, 607 98) and fluoroindole-N-sulfonyl acids 99, has also been reported [103]. These are compounds that are analogues of indomethacin 100 and achieve analgesic and antipyretic activity through the inhibition of cyclo-oxygenases [103].…”

Section: Non-steroidal Anti-inflammatory Drugsmentioning

confidence: 99%

Fluorine in medicinal chemistry: A review of anti-cancer agents

Isanbor

O’Hagan

2006

Journal of Fluorine Chemistry

1,015

343

View full text Add to dashboard Cite

“…Minor structural modification of ramatroban resulted in a highly selective and potent DP 2 antagonist (Ulven and Kostenis, 2005). Other indolic compounds with selective DP 2 receptor antagonist activities have also recently been reported (Armer et al, 2005;Birkinshaw et al, 2006). A series of tetrahydroquinoline derivatives have also been identified as selective DP 2 antagonists (Mimura et al, 2005).…”

Section: Effects Of 15r-pgdmentioning

confidence: 99%

Agonist and Antagonist Effects of 15R-Prostaglandin (PG) D₂and 11-Methylene-PGD₂on Human Eosinophils and Basophils

Cossette

Walsh²,

Kim³

et al. 2006

J Pharmacol Exp Ther

View full text Add to dashboard Cite

Prostaglandin (PG) D 2 acts through both the DP 1 receptor, which is coupled to adenylyl cyclase, and the DP 2 receptor (chemoattractant receptor-homologous molecule expressed on Th2 cells), which is present on eosinophils, basophils, and Th2 cells and results in cell activation and migration. The most potent prostanoid DP 2 agonist so far reported is 15R-methyl-PGD 2 , in which the hydroxyl group has the unnatural R configuration. In contrast, the corresponding analog possessing the natural 15S configuration is ϳ75 times less potent. This raised the question of whether the isoprostane 15R-PGD 2 might have potent DP 2 receptor-mediated biological activity. We therefore chemically synthesized 15R-PGD 2 and investigated its biological activity. This compound elicited DP 2 receptor-mediated CD11b expression in human basophils and eosinophils and induced actin polymerization and migration in eosinophils with a potency about the same as that of PGD 2 . In contrast, it had only a weak effect on DP 1 receptor-mediated adenylyl cyclase activity in human platelets. We also investigated the effects of modification of the 9-hydroxyl and 11-oxo groups of PGD 2 . Both PGK 2 , in which the 9-hydroxyl group is replaced by an oxo group, and 11-deoxy-11-methylene PGD 2 , in which the 11-oxo group is replaced by a CH 2 group, have little or no DP 1 or DP 2 agonist activity. However, the 11-methylene analog is a DP 2 antagonist (IC 50 , ϳ2 M). We conclude that 15R-PGD 2 , which may be generated by oxidative stress, is a potent and selective DP 2 agonist and that modification of the 11-oxo group of PGD 2 can result in DP 2 antagonist activity.

show abstract

Indole-3-acetic Acid Antagonists of the Prostaglandin D₂ Receptor CRTH2

Cited by 47 publications

References 20 publications

The Extracellular Signal-regulated Kinase Mitogen-activated Protein Kinase/Ribosomal S6 Protein Kinase 1 Cascade Phosphorylates cAMP Response Element-binding Protein to Induce MUC5B Gene Expression via d-Prostanoid Receptor Signaling

The Extracellular Signal-regulated Kinase Mitogen-activated Protein Kinase/Ribosomal S6 Protein Kinase 1 Cascade Phosphorylates cAMP Response Element-binding Protein to Induce MUC5B Gene Expression via d-Prostanoid Receptor Signaling

Fluorine in medicinal chemistry: A review of anti-cancer agents

Agonist and Antagonist Effects of 15R-Prostaglandin (PG) D₂and 11-Methylene-PGD₂on Human Eosinophils and Basophils

Contact Info

Product

Resources

About

Indole-3-acetic Acid Antagonists of the Prostaglandin D2 Receptor CRTH2

Cited by 47 publications

References 20 publications

The Extracellular Signal-regulated Kinase Mitogen-activated Protein Kinase/Ribosomal S6 Protein Kinase 1 Cascade Phosphorylates cAMP Response Element-binding Protein to Induce MUC5B Gene Expression via d-Prostanoid Receptor Signaling

The Extracellular Signal-regulated Kinase Mitogen-activated Protein Kinase/Ribosomal S6 Protein Kinase 1 Cascade Phosphorylates cAMP Response Element-binding Protein to Induce MUC5B Gene Expression via d-Prostanoid Receptor Signaling

Fluorine in medicinal chemistry: A review of anti-cancer agents

Agonist and Antagonist Effects of 15R-Prostaglandin (PG) D2and 11-Methylene-PGD2on Human Eosinophils and Basophils

Contact Info

Product

Resources

About

Indole-3-acetic Acid Antagonists of the Prostaglandin D₂ Receptor CRTH2

Agonist and Antagonist Effects of 15R-Prostaglandin (PG) D₂and 11-Methylene-PGD₂on Human Eosinophils and Basophils