期刊
ACS MEDICINAL CHEMISTRY LETTERS
卷 13, 期 4, 页码 648-657出版社
AMER CHEMICAL SOC
DOI: 10.1021/acsmedchemlett.1c00694
关键词
Serotonin 5-HT2 receptors; tetrahydro-beta-carbolines; small molecule agonists; heteroyohimbine metabolism
资金
- National Institutes of Health [R21NS120521]
- Northwestern University
- Medical College of Wisconsin Research Affairs Counsel Pilot Grant
- NIH [F30DA050445]
- Northwestern University's Chemistry of Life Processes Institute
This study identified a potential agonist activity of substituted tetrahydro-beta-carbolines across the 5-HT2 receptor family, laying a foundation for future research in neurological and psychiatric disorders.
The serotonin 5-HT2 receptors are important pharmaceutical targets involved in signaling pathways underlying various neurological, psychiatric, and cardiac functions and dysfunctions. As such, numerous ligands for the investigation of these receptors' activity and downstream effects have been developed synthetically or discovered in nature. For example, the heteroyohimbine natural product alstonine exhibits antispychotic activity mediated by 5-HT2A/2C agonism. In this work, we identified a heteroyohimbine metabolite containing a serotonin pharmacophore and truncated the scaffold, leading to the discovery of potent agonist activity of substituted tetrahydro-beta-carbolines across the 5-HT2 receptor family. Extensive SAR development resulted in compound 106 with EC50 values of 1.7, 0.58, and 0.50 nM at 5-HT2A, 5-HT2B, and 5-HT2C, respectively. Docking studies suggest a pi-stacking interaction between the tetrahydro-beta-carboline core and conserved residue Trp(6.48) as the structural basis for this activity. This work lays a foundation for future investigation of these compounds in neurological and psychiatric disorders.
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