The discovery of 071031B, a novel serotonin and noradrenaline reuptake inhibitor

• Published in: Neuroscience letters 2013-06, Vol.544, p.68-73
• Main Authors: Xue, Rui, Zhang, Yan-Ping, Jin, Zeng-Liang, Yuan, Li, He, Xin-Hua, Zhao, Nan, Chen, Hong-Xia, Zhang, Li-Ming, Fan, Shi-Yong, Zhong, Bo-Hua, Zhang, You-Zhi, Li, Yun-Feng
• Format: Article
• Language: English
• Subjects: Acute toxicity; Animals; Antidepressants; Antidepressive Agents - administration & dosage; Antidepressive Agents - chemistry; Antidepressive Agents - pharmacokinetics; Behavior, Animal - drug effects; Behavioral despair models; Depression - physiopathology; Depression - prevention & control; Dose-Response Relationship, Drug; Drug Evaluation, Preclinical - methods; Dual reuptake inhibitors; Female; Integrated evaluation system; Male; Mice; Mice, Inbred ICR; Monoamine transporters; Norepinephrine - antagonists & inhibitors; Serotonin Uptake Inhibitors - administration & dosage; Serotonin Uptake Inhibitors - pharmacokinetics; Survival Rate
• ISSN: 0304-3940; 1872-7972
• DOI: 10.1016/j.neulet.2013.02.076

•We establish a system to screen monoamine reuptake inhibitors fast and accurately.•Using this system, we discover a potential antidepressant 071031B.•071031B has robust antidepressant effect in vivo and transporter affinity in vitro.•071031B is expected to be a novel serotonin and noradrenaline reuptake inhibitor. Depression is a severe mood disorder with increasing morbidity and suicidality, while the current therapy is not satisfactory. Serotonin and noradrenaline reuptake inhibitors (SNRIs) have been reported to have higher efficacy and/or faster acting rate than commonly used antidepressants. The present study was designed to screen the potential SNRIs, using in vitro radioligand receptor binding assays and in vivo animal tests, and introduced the discovery of 071031B. In the tail suspension test and forced swimming test in mice, six compounds (071017S, 071026W, 071031A, 071031B, 080307A and 080307B) showed robust antidepressant activity, without stimulant effect on the locomotor activity or other side effects, and the minimal effective dose of 071017S, 071026W, 071031A and 071031B was less than that of duloxetine; in vitro binding tests indicated that 071031B had high affinity to both serotonin transporter and noradrenaline transporter with similar inhibitory rates to duloxetine at 1 and 100nM; acute toxicity test indicated that the LD50 value of 071031B was similar to that of duloxetine. These findings demonstrated that this integrated system, combining high throughput screening technology and in vivo animal tests, is effective to screen potential monoamine reuptake inhibitors fast and accurately; 071031B is expected to be a novel serotonin and noradrenaline reuptake inhibitor for its robust antidepressant activity and transporter affinity.