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

• Published in: Molecules
• Main Authors: Quxiang Li, Lili Ren, Dongli Wang, Junyong Luo, Changda Xu, Jian Feng, Yufan Qiu, Xiangqing Xu, Guoguang Chen
• Format: Article
• Language: English
• Published: MDPI AG 2024-11-01
• Subjects: amphetamine; multitarget; antidepressant; molecular docking
• Online Access: https://www.mdpi.com/1420-3049/29/22/5240
• ISSN: 1420-3049

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