Abstract
D prostanoid receptor 2 (DP₂) [also known as chemoattractant receptor-homologous molecule expressed on T helper 2 (Th2) cells (CRTH2)] is selectively expressed by Th2 lymphocytes, eosinophils, and basophils and mediates recruitment and activation of these cell types in response to prostaglandin D₂ (PGD₂). (5-Fluoro-2-methyl-3-quinolin-2-ylmethylindo-1-yl)-acetic acid (OC000459) is an indole-acetic acid derivative that potently displaces [³H]PGD₂ from human recombinant DP₂ (K(i) = 0.013 μM), rat recombinant DP₂ (K(i) = 0.003 μM), and human native DP₂ (Th2 cell membranes; K(i) = 0.004 μM) but does not interfere with the ligand binding properties or functional activities of other prostanoid receptors (prostaglandin E₁₋₄ receptors, D prostanoid receptor 1, thromboxane receptor, prostacyclin receptor, and prostaglandin F receptor). OC000459 inhibited chemotaxis (IC₅₀ = 0.028 μM) of human Th2 lymphocytes and cytokine production (IC₅₀ = 0.019 μM) by human Th2 lymphocytes. OC000459 competitively antagonized eosinophil shape change responses induced by PGD₂ in both isolated human leukocytes (pK(B) = 7.9) and human whole blood (pK(B) = 7.5) but did not inhibit responses to eotaxin, 5-oxo-eicosatetraenoic acid, or complement component C5a. OC000459 also inhibited the activation of Th2 cells and eosinophils in response to supernatants from IgE/anti-IgE-activated human mast cells. OC000459 had no significant inhibitory activity on a battery of 69 receptors and 19 enzymes including cyclooxygenase 1 (COX1) and COX2. OC000459 was found to be orally bioavailable in rats and effective in inhibiting blood eosinophilia induced by 13,14-dihydro-15-keto-PGD₂ (DK-PGD₂) in this species (ED₅₀ = 0.04 mg/kg p.o.) and airway eosinophilia in response to an aerosol of DK-PGD₂ in guinea pigs (ED₅₀ = 0.01 mg/kg p.o.). These data indicate that OC000459 is a potent, selective, and orally active DP₂ antagonist that retains activity in human whole blood and inhibits mast cell-dependent activation of both human Th2 lymphocytes and eosinophils.
MeSH terms
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Animals
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Apoptosis / drug effects
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Arachidonic Acids / pharmacology
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Binding, Competitive
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CHO Cells
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Calcium Signaling / drug effects
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Cell Membrane / metabolism
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Cell Shape / drug effects
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Cell Shape / immunology
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Chemokine CCL11 / pharmacology
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Chemotaxis / drug effects
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Chemotaxis / immunology
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Complement C5a / pharmacology
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Cricetinae
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Culture Media, Conditioned / pharmacology
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Eosinophilia / chemically induced
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Eosinophilia / prevention & control
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Eosinophils / cytology
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Eosinophils / drug effects*
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Eosinophils / immunology
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Guinea Pigs
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Humans
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Indoleacetic Acids / pharmacokinetics
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Indoleacetic Acids / pharmacology*
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Indoleacetic Acids / therapeutic use
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Interleukin-13 / metabolism
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Interleukin-5 / pharmacology
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Leukotriene B4 / pharmacology
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Lymphocyte Activation / drug effects*
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Lymphocyte Activation / immunology
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Mast Cells / immunology*
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Mast Cells / metabolism
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Prostaglandin Antagonists / pharmacokinetics
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Prostaglandin Antagonists / pharmacology*
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Prostaglandin Antagonists / therapeutic use
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Prostaglandin D2 / analogs & derivatives
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Prostaglandin D2 / metabolism
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Prostaglandin D2 / pharmacology
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Pulmonary Eosinophilia / chemically induced
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Pulmonary Eosinophilia / prevention & control
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Quinolines / pharmacokinetics
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Quinolines / pharmacology*
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Quinolines / therapeutic use
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Radioligand Assay
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Rats
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Rats, Sprague-Dawley
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Receptors, Immunologic / genetics
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Receptors, Immunologic / metabolism*
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Receptors, Prostaglandin / genetics
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Receptors, Prostaglandin / metabolism*
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Recombinant Proteins / metabolism
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Th2 Cells / cytology
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Th2 Cells / drug effects*
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Th2 Cells / immunology
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Th2 Cells / metabolism
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Transfection
Substances
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(5-fluoro-2-methyl-3-quinolin-2-ylmethylindo-1-yl)acetic acid
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Arachidonic Acids
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Chemokine CCL11
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Culture Media, Conditioned
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Indoleacetic Acids
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Interleukin-13
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Interleukin-5
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Prostaglandin Antagonists
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Quinolines
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Receptors, Immunologic
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Receptors, Prostaglandin
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Recombinant Proteins
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5-oxo-6,8,11,14-eicosatetraenoic acid
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Leukotriene B4
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13,14-dihydro-15-ketoprostaglandin D2
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Complement C5a
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Prostaglandin D2
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prostaglandin D2 receptor