title: 4-Chlorotetrazolo[1,5-a]quinoxaline inhibits activation of Syk kinase to suppress mast cells in vitro and mast cell-mediated passive cutaneous anaphylaxis in mice.
abstract: 4-Chlorotetrazolo[1,5-a]quinoxaline is a quinoxaline derivative. We aimed to study the effects of 4-chlorotetrazolo[1,5-a]quinoxaline on activation of mast cells in vitro and in mice. 4-Chlorotetrazolo[1,5-a]quinoxaline reversibly inhibited degranulation of mast cells in a dose-dependent manner, and also suppressed the expression and secretion of TNF-α and IL-4 in mast cells. Mechanistically, 4-chlorotetrazolo[1,5-a]quinoxaline inhibited activating phosphorylation of Syk and LAT, which are crucial for early FcεRI-mediated signaling events, as well as Akt and MAP kinases, which play essential roles in the production of various pro-inflammatory cytokines in mast cells. Notably, although 4-chlorotetrazolo[1,5-a]quinoxaline inhibited the activation of Fyn and Syk, minimal inhibition was observed in mast cells in the case of Lyn. Furthermore, consistent with its in vitro activity, 4-chlorotetrazolo[1,5-a]quinoxaline significantly suppressed mast cell-mediated passive cutaneous anaphylaxis in mice. In summary, the results from this study demonstrate that 4-chlorotetrazolo[1,5-a]quinoxaline shows an inhibitory effect on mast cells in vitro and in vivo, and that this is mediated by inhibiting the activation of Syk in mast cells. Therefore, 4-chlorotetrazolo[1,5-a]quinoxaline could be useful in the treatment of mast cell-mediated allergic diseases.
authors.affiliation: Center for Drug Development Assistance, National Institute of Food Drug Safety Evaluation, KFDA, Cheongwon-gun, Republic of Korea.
authors.forename: Kui Lea
authors.initials: KL
authors.lastname: Park
authors.forename: Na Young
authors.initials: NY
authors.lastname: Ko
authors.forename: Jun Ho
authors.initials: JH
authors.lastname: Lee
authors.forename: Do Kyun
authors.initials: DK
authors.lastname: Kim
authors.forename: Hyuk Soon
authors.initials: HS
authors.lastname: Kim
authors.forename: A-Ram
authors.initials: AR
authors.lastname: Kim
authors.forename: Erk
authors.initials: E
authors.lastname: Her
authors.forename: Bokyung
authors.initials: B
authors.lastname: Kim
authors.forename: Hyung Sik
authors.initials: HS
authors.lastname: Kim
authors.forename: Eun-Yi
authors.initials: EY
authors.lastname: Moon
authors.forename: Young Mi
authors.initials: YM
authors.lastname: Kim
authors.forename: Hang-Rae
authors.initials: HR
authors.lastname: Kim
authors.forename: Wahn Soo
authors.initials: WS
authors.lastname: Choi
mesh_terms: D000818:Animals; D004789:Enzyme Activation / Q000187:drug effects / Q000502:physiology; D047908:Intracellular Signaling Peptides and Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D008297:Male; D008407:Mast Cells / Q000187:drug effects* / Q000201:enzymology; D051379:Mice; D008807:Mice, Inbred BALB C; D010323:Passive Cutaneous Anaphylaxis / Q000187:drug effects* / Q000502:physiology; D047428:Protein Kinase Inhibitors / Q000633:toxicity*; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011810:Quinoxalines / Q000737:chemistry* / Q000633:toxicity*; D000072377:Syk Kinase
chemical_list: D047908:Intracellular Signaling Peptides and Proteins; D047428:Protein Kinase Inhibitors; D011810:Quinoxalines; D011505:Protein-Tyrosine Kinases; D000072377:Syk Kinase; C000606897:Syk protein, mouse