title: Antidepressant-like effects of 071031B, a novel serotonin and norepinephrine reuptake inhibitor.
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 10mg/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.
authors: Department of New Drug Evaluation, Beijing Institute of Pharmacology and Toxicology, 27 Taiping Road, Beijing 100850, PR China.
authors: Rui
authors: R
authors: Xue
authors: Zeng-Liang
authors: ZL
authors: Jin
authors: Hong-Xia
authors: HX
authors: Chen
authors: Li
authors: L
authors: Yuan
authors: Xin-Hua
authors: XH
authors: He
authors: Yan-Ping
authors: YP
authors: Zhang
authors: Yong-Gang
authors: YG
authors: Meng
authors: Jiang-Ping
authors: JP
authors: Xu
authors: Jian-Quan
authors: JQ
authors: Zheng
authors: Bo-Hua
authors: BH
authors: Zhong
authors: Yun-Feng
authors: YF
authors: Li
authors: You-Zhi
authors: YZ
authors: Zhang
mesh_terms: D000818:Animals; D000928:Antidepressive Agents / Q000737:chemistry / Q000494:pharmacology*; D001522:Behavior, Animal / Q000187:drug effects; D052117:Benzodioxoles / Q000737:chemistry / Q000494:pharmacology* / Q000633:toxicity; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000187:drug effects; D003342:Corpus Striatum / Q000187:drug effects; D050483:Dopamine Plasma Membrane Transport Proteins / Q000037:antagonists & inhibitors; D004305:Dose-Response Relationship, Drug; D000068736:Duloxetine Hydrochloride; D006801:Humans; D046353:Immobility Response, Tonic / Q000187:drug effects; D008297:Male; D051379:Mice; D015394:Molecular Structure; D009043:Motor Activity / Q000187:drug effects; D050484:Norepinephrine Plasma Membrane Transport Proteins / Q000037:antagonists & inhibitors*; D051381:Rats; D017367:Selective Serotonin Reuptake Inhibitors / Q000494:pharmacology*; D013574:Synaptosomes / Q000187:drug effects; D013876:Thiophenes / Q000737:chemistry / Q000494:pharmacology* / Q000633:toxicity
chemical_list: D000928:Antidepressive Agents; D052117:Benzodioxoles; D050483:Dopamine Plasma Membrane Transport Proteins; D000068736:Duloxetine Hydrochloride; D050484:Norepinephrine Plasma Membrane Transport Proteins; D017367:Selective Serotonin Reuptake Inhibitors; D013876:Thiophenes; C585814:071031B compound