Amphetamine Derivatives as Potent Central Nervous System Multitarget SERT/NET/H Agents: Synthesis and Biological Evaluation.

In this research, a variety of novel amphetamine derivatives were synthesized and assessed for their potential as multifaceted antidepressant agents. Among these compounds, compound demonstrated potent inhibitory effects on both serotonin and noradrenaline transporters (SERT/NET) and high affinity for histamine H receptor (HR), and displayed low affinity for off-target receptors (H1, α1) and hERG channels, which can reduce the prolongation of the QT interval. Molecular docking studies offered a rational binding model of compound when it forms a complex with SERT, NET, and the histamine H receptor. In vivo behavioral studies, compound dose-dependently reduced the immobility duration in the mouse FST and TST assays without a stimulatory effect on the locomotor activity. Furthermore, compound had a favorable pharmacokinetic profile in rats. Thus, compound has the potential to develop a novel class of drugs for the treatment of depression.