title: The discovery of 071031B, a novel serotonin and noradrenaline reuptake inhibitor.
abstract: 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 100 nM; 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.
authors.affiliation: Department of New Drug Evaluation, Beijing Institute of Pharmacology and Toxicology, Beijing, PR China.
authors.forename: Rui
authors.initials: R
authors.lastname: Xue
authors.forename: Yan-Ping
authors.initials: YP
authors.lastname: Zhang
authors.forename: Zeng-Liang
authors.initials: ZL
authors.lastname: Jin
authors.forename: Li
authors.initials: L
authors.lastname: Yuan
authors.forename: Xin-Hua
authors.initials: XH
authors.lastname: He
authors.forename: Nan
authors.initials: N
authors.lastname: Zhao
authors.forename: Hong-Xia
authors.initials: HX
authors.lastname: Chen
authors.forename: Li-Ming
authors.initials: LM
authors.lastname: Zhang
authors.forename: Shi-Yong
authors.initials: SY
authors.lastname: Fan
authors.forename: Bo-Hua
authors.initials: BH
authors.lastname: Zhong
authors.forename: You-Zhi
authors.initials: YZ
authors.lastname: Zhang
authors.forename: Yun-Feng
authors.initials: YF
authors.lastname: Li
mesh_terms: D000818:Animals; D000928:Antidepressive Agents / Q000008:administration & dosage* / Q000737:chemistry / Q000493:pharmacokinetics*; D001522:Behavior, Animal / Q000187:drug effects*; D003863:Depression / Q000503:physiopathology* / Q000517:prevention & control*; D004305:Dose-Response Relationship, Drug; D004353:Drug Evaluation, Preclinical / Q000379:methods; D005260:Female; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D009638:Norepinephrine / Q000037:antagonists & inhibitors*; D017367:Selective Serotonin Reuptake Inhibitors / Q000008:administration & dosage* / Q000493:pharmacokinetics; D015996:Survival Rate
chemical_list: D000928:Antidepressive Agents; D009638:Norepinephrine; D017367:Selective Serotonin Reuptake Inhibitors