A Novel Imidazo[1,5-b]isoquinolinone Derivative, U63A05, Inhibits Syk Activation in Mast Cells to Suppress IgE-Mediated Anaphylaxis in Mice

Mast cells play a pivotal role in IgE-mediated allergic responses. Development of specific inhibitors against FcεRI-associated proximal signaling molecules in mast cells may represent a promising therapeutic strategy for allergic diseases. We examined whether a novel synthetic compound, 3-butyl-1-ch...

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Main Authors:	Do Kyun Kim, Jun Ho Lee, Jie Wan Kim, Hyuk Soon Kim, A-Ram Kim, Bo Kyung Kim, Kyu Yang Yi, Hye-Jin Park, Dong Ki Park, Wahn Soo Choi
Format:	Article
Language:	English
Published:	Elsevier 2011-01-01
Series:	Journal of Pharmacological Sciences
Online Access:	http://www.sciencedirect.com/science/article/pii/S1347861319307455

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spelling	doaj-147d2a5ef5cc4c73a8c3aaef7b5a6f4b2020-11-25T01:07:26ZengElsevierJournal of Pharmacological Sciences1347-86132011-01-011154500508A Novel Imidazo[1,5-b]isoquinolinone Derivative, U63A05, Inhibits Syk Activation in Mast Cells to Suppress IgE-Mediated Anaphylaxis in MiceDo Kyun Kim0Jun Ho Lee1Jie Wan Kim2Hyuk Soon Kim3A-Ram Kim4Bo Kyung Kim5Kyu Yang Yi6Hye-Jin Park7Dong Ki Park8Wahn Soo Choi9Institutes of Functional Genomics and College of Medicine, Konkuk University, Chungju 380-701, KoreaInstitutes of Functional Genomics and College of Medicine, Konkuk University, Chungju 380-701, KoreaInstitutes of Functional Genomics and College of Medicine, Konkuk University, Chungju 380-701, KoreaInstitutes of Functional Genomics and College of Medicine, Konkuk University, Chungju 380-701, KoreaInstitutes of Functional Genomics and College of Medicine, Konkuk University, Chungju 380-701, KoreaInstitutes of Functional Genomics and College of Medicine, Konkuk University, Chungju 380-701, KoreaBio-Organic Science Division, Korea Research Institute of Chemical Technology, Daejeon 305-600, KoreaDepartment of Bioscience and Biotechnology, Konkuk University, Seoul 13-701, KoreaDepartment of Bioscience and Biotechnology, Konkuk University, Seoul 13-701, KoreaInstitutes of Functional Genomics and College of Medicine, Konkuk University, Chungju 380-701, Korea; Corresponding author. wahnchoi@kku.ac.krMast cells play a pivotal role in IgE-mediated allergic responses. Development of specific inhibitors against FcεRI-associated proximal signaling molecules in mast cells may represent a promising therapeutic strategy for allergic diseases. We examined whether a novel synthetic compound, 3-butyl-1-chloro-8-(2-methoxycarbonyl)phenyl-5H-imidazo[1,5-b]isoquinolin-10-one (U63A05), could suppress antigen-stimulated degranulation and cytokine secretion in mast cells and IgE-mediated passive cutaneous anaphylaxis (PCA) in mice. U63A05 reversibly and dose-dependently inhibited degranulation of rat basophilic leukemia (RBL)-2H3 mast cells and bone marrow–derived mast cells (BMMCs) stimulated by antigen (IC50 values for RBL-2H3 and BMMCs were 4.1 and 4.8 μM, respectively). The secretion of inflammatory cytokines was also suppressed in antigen-stimulated mast cells. However, degranulation by thapsigargin, a typical calcium inducer, was not inhibited by U63A05. U63A05 exerts its inhibitory effect, to the same extent as in degranulation, on the activating phosphorylation of Syk and downstream signaling molecules, including LAT and SLP-76. Further downstream, the activating phosphorylations of Akt, Erk1/2, p38, and JNK were also inhibited. Finally, antigen-stimulated PCA was dose-dependently suppressed in mice (ED50, 26.3 mg/kg). Taken together, the results suggest that U63A05 suppresses the activation of mast cells and the mast cell–mediated allergic response through the inhibition of Syk activation in mast cells. Keywords:: 3-butyl-1-chloro-8-(2-methoxycarbonyl)phenyl-5H-imidazo[1,5-b]isoquinolin-10-one (U63A05), mast cell, IgE, type I hypersensitive response, sykhttp://www.sciencedirect.com/science/article/pii/S1347861319307455
collection	DOAJ
language	English
format	Article
sources	DOAJ
author	Do Kyun Kim Jun Ho Lee Jie Wan Kim Hyuk Soon Kim A-Ram Kim Bo Kyung Kim Kyu Yang Yi Hye-Jin Park Dong Ki Park Wahn Soo Choi
spellingShingle	Do Kyun Kim Jun Ho Lee Jie Wan Kim Hyuk Soon Kim A-Ram Kim Bo Kyung Kim Kyu Yang Yi Hye-Jin Park Dong Ki Park Wahn Soo Choi A Novel Imidazo[1,5-b]isoquinolinone Derivative, U63A05, Inhibits Syk Activation in Mast Cells to Suppress IgE-Mediated Anaphylaxis in Mice Journal of Pharmacological Sciences
author_facet	Do Kyun Kim Jun Ho Lee Jie Wan Kim Hyuk Soon Kim A-Ram Kim Bo Kyung Kim Kyu Yang Yi Hye-Jin Park Dong Ki Park Wahn Soo Choi
author_sort	Do Kyun Kim
title	A Novel Imidazo[1,5-b]isoquinolinone Derivative, U63A05, Inhibits Syk Activation in Mast Cells to Suppress IgE-Mediated Anaphylaxis in Mice
title_short	A Novel Imidazo[1,5-b]isoquinolinone Derivative, U63A05, Inhibits Syk Activation in Mast Cells to Suppress IgE-Mediated Anaphylaxis in Mice
title_full	A Novel Imidazo[1,5-b]isoquinolinone Derivative, U63A05, Inhibits Syk Activation in Mast Cells to Suppress IgE-Mediated Anaphylaxis in Mice
title_fullStr	A Novel Imidazo[1,5-b]isoquinolinone Derivative, U63A05, Inhibits Syk Activation in Mast Cells to Suppress IgE-Mediated Anaphylaxis in Mice
title_full_unstemmed	A Novel Imidazo[1,5-b]isoquinolinone Derivative, U63A05, Inhibits Syk Activation in Mast Cells to Suppress IgE-Mediated Anaphylaxis in Mice
title_sort	novel imidazo[1,5-b]isoquinolinone derivative, u63a05, inhibits syk activation in mast cells to suppress ige-mediated anaphylaxis in mice
publisher	Elsevier
series	Journal of Pharmacological Sciences
issn	1347-8613
publishDate	2011-01-01
description	Mast cells play a pivotal role in IgE-mediated allergic responses. Development of specific inhibitors against FcεRI-associated proximal signaling molecules in mast cells may represent a promising therapeutic strategy for allergic diseases. We examined whether a novel synthetic compound, 3-butyl-1-chloro-8-(2-methoxycarbonyl)phenyl-5H-imidazo[1,5-b]isoquinolin-10-one (U63A05), could suppress antigen-stimulated degranulation and cytokine secretion in mast cells and IgE-mediated passive cutaneous anaphylaxis (PCA) in mice. U63A05 reversibly and dose-dependently inhibited degranulation of rat basophilic leukemia (RBL)-2H3 mast cells and bone marrow–derived mast cells (BMMCs) stimulated by antigen (IC50 values for RBL-2H3 and BMMCs were 4.1 and 4.8 μM, respectively). The secretion of inflammatory cytokines was also suppressed in antigen-stimulated mast cells. However, degranulation by thapsigargin, a typical calcium inducer, was not inhibited by U63A05. U63A05 exerts its inhibitory effect, to the same extent as in degranulation, on the activating phosphorylation of Syk and downstream signaling molecules, including LAT and SLP-76. Further downstream, the activating phosphorylations of Akt, Erk1/2, p38, and JNK were also inhibited. Finally, antigen-stimulated PCA was dose-dependently suppressed in mice (ED50, 26.3 mg/kg). Taken together, the results suggest that U63A05 suppresses the activation of mast cells and the mast cell–mediated allergic response through the inhibition of Syk activation in mast cells. Keywords:: 3-butyl-1-chloro-8-(2-methoxycarbonyl)phenyl-5H-imidazo[1,5-b]isoquinolin-10-one (U63A05), mast cell, IgE, type I hypersensitive response, syk
url	http://www.sciencedirect.com/science/article/pii/S1347861319307455
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A Novel Imidazo[1,5-b]isoquinolinone Derivative, U63A05, Inhibits Syk Activation in Mast Cells to Suppress IgE-Mediated Anaphylaxis in Mice

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