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Eur J Med Chem. 2016 Jul 19;117:19-32. doi: 10.1016/j.ejmech.2016.04.017. Epub 2016 Apr 9.

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.

Author information

1
School of Pharmacy, Shanghai Jiao Tong University, 800 Dongchuan Road, Shanghai 200240, China.
2
School of Pharmacy, Shanghai Jiao Tong University, 800 Dongchuan Road, Shanghai 200240, China. Electronic address: leifu@sjtu.edu.cn.
3
School of Pharmacy, Shanghai Jiao Tong University, 800 Dongchuan Road, Shanghai 200240, China. Electronic address: yxwang@sjtu.edu.cn.

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.

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

PMID:
27089209
DOI:
10.1016/j.ejmech.2016.04.017
[Indexed for MEDLINE]

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