Amphetamine Derivatives as Potent Central Nervous System Multitarget SERT/NET/H 3 Agents: Synthesis and Biological Evaluation.

Publisher: MDPI Country of Publication: Switzerland NLM ID: 100964009 Publication Model: Electronic Cited Medium: Internet ISSN: 1420-3049 (Electronic) Linking ISSN: 14203049 NLM ISO Abbreviation: Molecules Subsets: MEDLINE

Original Publication: Basel, Switzerland : MDPI, c1995-

Molecular Docking Simulation* ; Serotonin Plasma Membrane Transport Proteins*/metabolism ; Receptors, Histamine H3*/metabolism ; Antidepressive Agents*/pharmacology ; Antidepressive Agents*/chemical synthesis ; Antidepressive Agents*/chemistry ; Antidepressive Agents*/pharmacokinetics; Animals ; Mice ; Humans ; Rats ; Norepinephrine Plasma Membrane Transport Proteins/metabolism ; Amphetamine/pharmacology ; Amphetamine/chemical synthesis ; Structure-Activity Relationship ; Central Nervous System/drug effects ; Central Nervous System/metabolism ; Male ; Amphetamines/pharmacology ; Amphetamines/chemical synthesis ; Amphetamines/chemistry

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 H 3 receptor (H 3 R), 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 H 3 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.

2017ZX0931057,BE2019738,2023YFF0723400,BM2019004 National Science and Technology Major Project (2017ZX0931057), Jiangsu key R&D plan (BE2019738), National Key R&D Program of China (2023YFF0723400) and Jiangsu Key Laboratory of Central Nervous System Drug Research and Development (BM2019004)

Keywords: amphetamine; antidepressant; molecular docking; multitarget

0 (Serotonin Plasma Membrane Transport Proteins)
0 (Receptors, Histamine H3)
0 (Antidepressive Agents)
0 (Norepinephrine Plasma Membrane Transport Proteins)
CK833KGX7E (Amphetamine)
0 (Amphetamines)

Date Created: 20241127 Date Completed: 20241127 Latest Revision: 20241127

20241202

10.3390/molecules29225240

39598630