Discovery of Highly Potent Serotonin 5-HT₂ Receptor Agonists Inspired by Heteroyohimbine Natural Products.

ABSTRACT: 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-HT_2A/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-β-carbolines across the 5-HT₂ receptor family. Extensive SAR development resulted in compound 106 with

SUBMITTER: Orr MJ 

PROVIDER: S-EPMC9014500 | biostudies-literature | 2022 Apr

REPOSITORIES: biostudies-literature