title: Discovery and analgesic evaluation of 8-chloro-1,4-dihydropyrido[2,3-b]pyrazine-2,3-dione as a novel potent d-amino acid oxidase inhibitor.
abstract: A series of 5-azaquinoxaline-2,3-dione derivatives were synthesized and evaluated on d-amino acid oxidase (DAAO) inhibition as potential α-hydroxylactam-based inhibitors. The potent inhibitory activities in vitro suggested that 5-nitrogen could significantly enhance the binding affinity by strengthening relevant hydrogen bond interactions. The analgesic effects of intrathecal and systemic injection of 8-chloro-1,4-dihydropyrido[2,3-b]pyrazine-2,3-dione, a representative molecule of 5-azaquinoxaline-2,3-dione, were investigated in rodents. This research not only confirmed the analgesic effect of the DAAO inhibitors but provided a new class of chemical entities with oral application potential for the treatment of chronic pain and morphine analgesic tolerance.
authors.affiliation: School of Pharmacy, Shanghai Jiao Tong University, 800 Dongchuan Road, Shanghai 200240, China.
authors.forename: Dongsheng
authors.initials: D
authors.lastname: Xie
authors.affiliation: School of Pharmacy, Shanghai Jiao Tong University, 800 Dongchuan Road, Shanghai 200240, China.
authors.forename: Jun
authors.initials: J
authors.lastname: Lu
authors.affiliation: School of Pharmacy, Shanghai Jiao Tong University, 800 Dongchuan Road, Shanghai 200240, China.
authors.forename: Jin
authors.initials: J
authors.lastname: Xie
authors.affiliation: School of Pharmacy, Shanghai Jiao Tong University, 800 Dongchuan Road, Shanghai 200240, China.
authors.forename: Junjun
authors.initials: J
authors.lastname: Cui
authors.affiliation: School of Pharmacy, Shanghai Jiao Tong University, 800 Dongchuan Road, Shanghai 200240, China.
authors.forename: Teng-Fei
authors.initials: TF
authors.lastname: Li
authors.affiliation: School of Pharmacy, Shanghai Jiao Tong University, 800 Dongchuan Road, Shanghai 200240, China.
authors.forename: Yan-Chao
authors.initials: YC
authors.lastname: Wang
authors.affiliation: School of Pharmacy, Shanghai Jiao Tong University, 800 Dongchuan Road, Shanghai 200240, China.
authors.forename: Yuan
authors.initials: Y
authors.lastname: Chen
authors.affiliation: School of Pharmacy, Shanghai Jiao Tong University, 800 Dongchuan Road, Shanghai 200240, China.
authors.forename: Nian
authors.initials: N
authors.lastname: Gong
authors.affiliation: School of Pharmacy, Shanghai Jiao Tong University, 800 Dongchuan Road, Shanghai 200240, China.
authors.forename: Xin-Yan
authors.initials: XY
authors.lastname: Li
authors.affiliation: School of Pharmacy, Shanghai Jiao Tong University, 800 Dongchuan Road, Shanghai 200240, China. Electronic address: leifu@sjtu.edu.cn.
authors.forename: Lei
authors.initials: L
authors.lastname: Fu
authors.affiliation: School of Pharmacy, Shanghai Jiao Tong University, 800 Dongchuan Road, Shanghai 200240, China. Electronic address: yxwang@sjtu.edu.cn.
authors.forename: Yong-Xiang
authors.initials: YX
authors.lastname: Wang
mesh_terms: D000700:Analgesics / Q000138:chemical synthesis* / Q000494:pharmacology; D000818:Animals; D003605:D-Amino-Acid Oxidase / Q000037:antagonists & inhibitors*; D055808:Drug Discovery / Q000379:methods; D004361:Drug Tolerance; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology; D051379:Mice; D009020:Morphine / Q000494:pharmacology; D011810:Quinoxalines / Q000138:chemical synthesis* / Q000494:pharmacology
chemical_list: D000700:Analgesics; D004791:Enzyme Inhibitors; D011810:Quinoxalines; D009020:Morphine; C485958:Dao1 protein, mouse; D003605:D-Amino-Acid Oxidase
keywords: 5-Azaquinoxaline-2,3-diones; 8-Chloro-1,4-dihydropyrido[2,3-b]pyrazine-2,3-dione; Analgesic effects; D-amino acid oxidase; DAAO inhibitors