Heterocycle-fused phenylcyclohexylamines as novel multi-target antagonists of N-methyl-D-aspartate (NMDA) receptor and monoamine transporter for treating depression.

Simultaneously modulating the glutamatergic and monoaminergic systems represents a promising strategy for treating depression. In this study, a series of multi-target antagonists targeting both NMDAR and monoamine transporters (SERT, DAT, and NET) was designed and evaluated for their antidepressant potential in vitro and in vivo. Among these heterocycle-fused phenylcyclohexylamine derivatives, compound A16 demonstrated potent and relatively balanced multi-target activity (A16: IC50(NMDAR): IC50(SERT): IC50(DAT): IC50(NET) = 1.8:1.0:1.9:1.3) compared to the lead compound S1. Pharmacokinetic studies revealed that A16 exhibited moderate clearance in microsomes and favorable oral brain exposure in mice. In vivo assessments showed that A16 and its R-isomer A17 exhibited significant antidepressant-like effects in the forced swim test and tail suspension test in mice. Notably, A17 demonstrated significant antidepressant-like effects at doses as low as 1 mg/kg, with no indication of addiction risk at 20 mg/kg. Collectively, these findings identify A17, a heterocycle-fused phenylcyclohexylamine as a promising scaffold for developing non-addictive, rapid-acting antidepressants.