Antidepressant-like effects of 071031B, a novel serotonin and norepinephrine reuptake inhibitor

• Published in: European neuropsychopharmacology 2013-07, Vol.23 (7), p.728-741
• Main Authors: Xue, Rui, Jin, Zeng-Liang, Chen, Hong-Xia, Yuan, Li, He, Xin-Hua, Zhang, Yan-Ping, Meng, Yong-Gang, Xu, Jiang-Ping, Zheng, Jian-Quan, Zhong, Bo-Hua, Li, Yun-Feng, Zhang, You-Zhi
• Format: Article
• Language: English
• Subjects: Animal models; Animals; Antidepressants; Antidepressive Agents - chemistry; Antidepressive Agents - pharmacology; Behavior, Animal - drug effects; Benzodioxoles - chemistry; Benzodioxoles - pharmacology; Benzodioxoles - toxicity; Cells, Cultured; Cerebral Cortex - drug effects; Corpus Striatum - drug effects; Cytotoxicity test; Dopamine Plasma Membrane Transport Proteins - antagonists & inhibitors; Dose-Response Relationship, Drug; Duloxetine Hydrochloride; Humans; Immobility Response, Tonic - drug effects; Internal Medicine; Male; Mice; Molecular Structure; Monoamine transporter binding test; Monoamine uptake test; Motor Activity - drug effects; Norepinephrine Plasma Membrane Transport Proteins - antagonists & inhibitors; Psychiatry; Rats; Serotonin and norepinephrine uptake inhibitors; Serotonin Uptake Inhibitors - pharmacology; Synaptosomes - drug effects; Thiophenes - chemistry; Thiophenes - pharmacology; Thiophenes - toxicity
• ISSN: 0924-977X; 1873-7862
• DOI: 10.1016/j.euroneuro.2012.06.001

Abstract SNRIs (serotonin and norepinephrine reuptake inhibitors) have been proposed to exert increased therapeutic efficacy or be faster acting compared to commonly used antidepressants. In this study, we performed in vitro binding and uptake assays and in vivo behavioral tests to assess the pharmacological properties and antidepressant-like efficacy of the compound 071031B; we also performed cytotoxicity tests using HepG2 cells and SH-SY5Y cells to predict the toxicity of 071031B. In vitro, 071031B had high affinity for both serotonin transporters and norepinephrine transporters prepared from rat cortex tissue ( Ki =2.68 and 1.09 nM, respectively) and recombinant cells ( Ki =1.57 and 0.36 nM, respectively). Moreover, 071031B also potently inhibited the uptake of serotonin (5-HT) and norepinephrine (NE) into rat cortical synaptosomes ( Ki =1.99 and 1.09 nM, respectively) and recombinant cells ( Ki =3.23 and 0.79 nM, respectively). In vivo, acute administration of 071031B dose-dependently reduced the immobility time in the tail suspension test in mice and the forced swimming test in mice and rats with higher efficacy than duloxetine and showed no stimulatory effect on the locomotor activity. Chronic 071031B treatment (5 or 10 mg/kg) significantly reversed depressive-like behaviors in chronically stressed rats, including reduced sucrose preference, decreased locomotor activity, and prolonged latency to begin eating. Furthermore, 071031B also exhibited lower cytotoxicity in HepG2 cells and SH-SY5Y cells in vitro than duloxetine. These findings suggest that 071031B is a novel, balanced serotonin and norepinephrine reuptake inhibitor, with more potent antidepressant effects and lower hepatotoxicity and neurotoxicity in vitro than duloxetine.