# Amphetamine Derivatives as Potent Central Nervous System Multitarget SERT/NET/H3 Agents: Synthesis and Biological Evaluation

## TL;DR

Scientists created new amphetamine-like compounds that may treat depression by targeting multiple brain receptors and showed promising results in animal tests.

## Contribution

A novel amphetamine derivative, compound 11b, was developed with multitarget activity and favorable safety and pharmacokinetic profiles.

## Key findings

- Compound 11b inhibits serotonin and noradrenaline transporters and binds to histamine H3 receptors with high affinity.
- Compound 11b reduced immobility in mouse behavioral tests for depression without affecting locomotor activity.
- Compound 11b has a favorable pharmacokinetic profile in rats and low affinity for off-target receptors and hERG channels.

## Abstract

In this research, a variety of novel amphetamine derivatives were synthesized and assessed for their potential as multifaceted antidepressant agents. Among these compounds, compound 11b demonstrated potent inhibitory effects on both serotonin and noradrenaline transporters (SERT/NET) and high affinity for histamine H3 receptor (H3R), 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 11b when it forms a complex with SERT, NET, and the histamine H3 receptor. In vivo behavioral studies, compound 11b dose-dependently reduced the immobility duration in the mouse FST and TST assays without a stimulatory effect on the locomotor activity. Furthermore, compound 11b had a favorable pharmacokinetic profile in rats. Thus, compound 11b has the potential to develop a novel class of drugs for the treatment of depression.