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 EC₅₀ values of 1.7, 0.58, and 0.50 nM at 5-HT_2A, 5-HT_2B, and 5-HT_2C, respectively. Docking studies suggest a π-stacking interaction between the tetrahydro-β-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.