Evaluation of the Indazole Analogs of 5-MeO-DMT and Related Tryptamines as Serotonin Receptor 2 Agonists.
ACS medicinal chemistry letters February 8, 2024 Navoda Jayakodiarachchi, Mallory A Maurer, Daniel C Schultz et al. 6 citations
A new set of indazole-based compounds was synthesized and tested as potent agonists of the serotonin 5-HT2 receptor subtypes. The direct indazole analogs of 5-MeO-DMT showed strong activity, but many, including the optimized compound VU6067416 (19d), also acted as potent 5-HT2B agonists, which prevented further development due to safety concerns. Computational docking studies suggest that the high potency of 19d may arise from a halogen-bonding interaction with Phe2345.38 in the 5-HT2A binding pocket. The work underscores the importance of rigorous subtype selectivity profiling for these serotonergic compounds.