Synthesis and biological evaluation of multimodal monoaminergic arylpiperazine derivatives with potential antidepressant profile

Depression is a common psychiatric disorder with an estimated global prevalence of 4.4 %. Here, we designed a series of new multimodal monoaminergic arylpiperazine derivatives using a pharmacophore hybrid approach and synthesized them for the treatment of depression. Molecular docking was employed to elucidate the differences in activity and selectivity of the corresponding compounds on SERT, NET, and DAT. In vitro experiments demonstrated that compound A3 has a relatively balanced multi-target activity profile with SERT reuptake inhibition (IC₅₀ = 12 nM), NET reuptake inhibition (IC₅₀ = 78 nM), DAT reuptake inhibition (IC₅₀ = 135 nM), and 5-HT_1AR agonism (EC₅₀ = 34 nM). Pharmacokinetic experiments revealed that A3 exhibited excellent bioavailability and low clearance in mice. Subsequent behavioral experiments further confirmed its significant antidepressant effects. These results further highlight the rationality of our design strategy.