title: The Inhibitory Effect of S-777469, a Cannabinoid Type 2 Receptor Agonist, on Skin Inflammation in Mice.
abstract: We investigated the effects of S-777469 (1-[[6-Ethyl-1-[4-fluorobenzyl]-5-methyl-2-oxo-1, 2-dihydropyridine-3-carbonyl]amino]-cyclohexanecarboxylic acid), a novel cannabinoid type 2 receptor (CB2) agonist, on 1-fluoro-2,4-dinitrobenzene (DNFB)-induced ear inflammation and mite antigen-induced dermatitis in mice. The oral administration of S-777469 significantly suppressed DNFB-induced ear swelling in a dose-dependent manner. In addition, S-777469 significantly alleviated mite antigen-induced atopic dermatitis-like skin lesions in NC/Nga mice. A histological analysis revealed that S-777469 significantly reduced the epidermal thickness and the number of mast cells infiltrating skin lesions. We demonstrated that S-777469 inhibited mite antigen-induced eosinophil accumulation in skin lesions and an endogenous CB2 ligand, 2-arachidonoylglycerol (2-AG)-induced eosinophil migration in vitro. Moreover, we confirmed that 2-AG levels significantly increased in skin lesions of mite antigen-induced dermatitis model. Together, these results suggest that S-777469 inhibits skin inflammation in mice by blocking the activities of 2-AG.
authors.affiliation: Drug Discovery and Disease Research Laboratory,SHIONOGI &amp; Co., Ltd., Osaka, Japan.
authors.forename: Takayo
authors.initials: T
authors.lastname: Haruna
authors.forename: Masahiko
authors.initials: M
authors.lastname: Soga
authors.forename: Yasuhide
authors.initials: Y
authors.lastname: Morioka
authors.forename: Kinichi
authors.initials: K
authors.lastname: Imura
authors.forename: Yoko
authors.initials: Y
authors.lastname: Furue
authors.forename: Mina
authors.initials: M
authors.lastname: Yamamoto
authors.forename: Jun
authors.initials: J
authors.lastname: Hayakawa
authors.forename: Masashi
authors.initials: M
authors.lastname: Deguchi
authors.forename: Akinori
authors.initials: A
authors.lastname: Arimura
authors.forename: Kiyoshi
authors.initials: K
authors.lastname: Yasui
mesh_terms: D000818:Animals; D001095:Arachidonic Acids / Q000037:antagonists & inhibitors / Q000378:metabolism; D054441:Cell Migration Assays, Leukocyte; D003876:Dermatitis, Atopic / Q000188:drug therapy / Q000378:metabolism; D004139:Dinitrofluorobenzene; D004305:Dose-Response Relationship, Drug; D063388:Endocannabinoids / Q000037:antagonists & inhibitors / Q000378:metabolism; D005989:Glycerides / Q000037:antagonists & inhibitors / Q000378:metabolism; D007249:Inflammation / Q000139:chemically induced / Q000188:drug therapy*; D008297:Male; D051379:Mice; D008924:Mite Infestations / Q000188:drug therapy / Q000378:metabolism; D011728:Pyridones / Q000494:pharmacology* / Q000627:therapeutic use*; D043885:Receptor, Cannabinoid, CB2 / Q000819:agonists*; D012867:Skin / Q000187:drug effects* / Q000473:pathology*
chemical_list: D001095:Arachidonic Acids; C571431:Cnr2 protein, mouse; D063388:Endocannabinoids; D005989:Glycerides; D011728:Pyridones; D043885:Receptor, Cannabinoid, CB2; C574957:S-777469; C094503:glyceryl 2-arachidonate; D004139:Dinitrofluorobenzene