Antidepressant-like Effects of ZBH2012001, a Novel Potent Serotonin and Norepinephrine Reuptake Inhibitor.

Abstract

The present study was conducted to evaluate the antidepressant-like effects of ZBH2012001, a novel potential serotonin and norepinephrine reuptake inhibitor (SNRI). Competitive binding assays, calcium flow, and cAMP detection methods were used to determine the affinity of ZBH2012001 for serotonin transporters (SERTs) and norepinephrine transporters (NETs), as well as its selectivity over dopamine transporters (DATs) and 16 other G-protein-coupled receptors (GPCRs) or iron channels. The antidepressant-like effects of ZBH2012001 were determined using the tail suspension test, forced swim test, and learned helplessness paradigm. The pharmacokinetics and acute toxicity of ZBH2012001 were also assessed. ZBH2012001 exhibited a moderate affinity to SERTs and NETs (Ki values were 35.3 ± 2.86 and 225 ± 26.0 nM, respectively); it had no effects on the DATs or the 16 other GPCRs or iron channels. Data from behavioral tests indicated that ZBH2012001 exhibited superior antidepressant-like effects compared with duloxetine (one of the most used SNRIs) in the three depression models. The pharmacokinetic evaluation of ZBH2012001 indicated that the absolute bioavailability value was 60.5%, and the acute toxicity test indicated that LD50 of ZBH2012001 was 346 mg/kg. These findings suggest that ZBH2012001 is a novel SNRI with superior antidepressant-like effects, lower acute toxicity and a better pharmacokinetic profile compared with duloxetine. Thus, ZBH2012001 may have potential therapeutic effects in depression disorders.