Neuropharmacological and antidepressant-like effects of ZY-1408: A novel serotonin/norepinephrine reuptake inhibitor and serotonin receptor 2C antagonist

Depression is a common mental illness and leading cause of disability. Most current antidepressants are associated with significant limitations, and in particular, a delayed onset and low rate of efficacy. Consequently, there remains an ongoing need for antidepressants that are either more effective or better tolerated than existing standards. We previously identified ZY-1408 as a drug with a novel chemical structure and potential anti-depressant-like activity. Specifically, ZY-1408 is a novel serotonin 2C (5-HT2C) receptor antagonist and serotonin/norepinephrine (5-HT/NE) reuptake inhibitor. In this study, we further investigated the antidepressant-like efficacy of ZY-1408 using in vitro and in vivo behavioral tests. ZY-1408 showed 5-HT2C receptor antagonist and 5-HT/NE reuptake inhibitor properties in vitro. Meanwhile, ZY-1408 decreased immobility in vivo in a dose-dependent manner in rats (via the forced-swim test) and mice (via the tail-suspension test). The behavioral test results do not appear to result from stimulation of locomotor activity. In chronically stressed rats, repeated ZY-1408 treatment significantly reversed depressive-like behavior, including reduced sucrose preference, decreased locomotor activity, and prolonged time to begin eating. Furthermore, in vivo microdialysis showed that administration of ZY-1408 significantly increased extracellular concentrations of 5-HT and NE in the hippocampus of freely moving rats. Thus, ZY-1408 is a potent and orally active 5-HT2C receptor antagonist and 5-HT/NE reuptake inhibitor with antidepressant-like activity in rodents.