2022/03/18 by Meghan J. Orr, Andrew B. Cao, Charles Tiancheng Wang +6 · 1 citation
Chemistry · Biochemistry, Genetics and Molecular Biology · Psychology · #Chemical synthesis and alkaloids #Synthesis and bioactivity of alkaloids #Psychedelics and Drug Studies
paper · doi:10.1021/acsmedchemlett.1c00694
openalex publication_date 2022/03/18 · openalex created_date 2022/04/03 · openalex updated_date 2026/08/01
The serotonin 5-HT 2 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-HT 2 receptor family. Extensive SAR development resulted in compound 106 with EC 50 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.