PUBLICATION
Development of MAO-A and 5-HT2AR Dual Inhibitors with Improved Antidepressant Activity
- Authors
- Sun, X., Li, N., Zhong, P., Chen, L., Sun, J.
- ID
- ZDB-PUB-220930-10
- Date
- 2022
- Source
- Journal of medicinal chemistry 65(19): 13385-13400 (Journal)
- Registered Authors
- Keywords
- none
- MeSH Terms
-
- Animals
- Antidepressive Agents/pharmacology
- Antidepressive Agents/therapeutic use
- Mice
- Monoamine Oxidase/metabolism
- Monoamine Oxidase Inhibitors*/chemistry
- Monoamine Oxidase Inhibitors*/pharmacology
- Monoamine Oxidase Inhibitors*/therapeutic use
- Oxygen
- Serotonin*
- Zebrafish/metabolism
- PubMed
- 36173886 Full text @ J. Med. Chem.
Citation
Sun, X., Li, N., Zhong, P., Chen, L., Sun, J. (2022) Development of MAO-A and 5-HT2AR Dual Inhibitors with Improved Antidepressant Activity. Journal of medicinal chemistry. 65(19):13385-13400.
Abstract
Designing dual-target inhibitors targeting 5-HT2AR and MAO-A could synergistically promote interstitial 5-HT levels, so as to exhibit a more efficient antidepressant effect. On the premise of maintaining the original pharmacophore binding, arylpiperazine scaffolds and 5-oxygen-substituted oxoisoaporphines were hybridized to afford 15 dual-target inhibitors through suitable linkers. Among all inhibitors, I14 exhibited the best inhibitory activities against 5-HT2AR and MAO-A. In vitro cell proliferation assays showed that most compounds were nontoxic to neuronal cells and normal hepatocytes. I14 also significantly ameliorated the depression-like behavior of zebrafish and mice. Further study revealed that I14 was able to occupy the active cavity of 5-HT2AR and MAO-A with multiple hydrogen bonding forces and π-π stacking interaction. I14 was also able to repair the damage of mice hippocampal neuronal cells and reduce the expression of 5-HT2AR in mice brain tissue. In conclusion, I14 could be a potential antidepressant candidate for further study.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping