Structural Pharmacology of Bufotenine Derivatives in Activating the 5-HT _1A Receptor for Therapeutic Potential in Depression and Anxiety

The 5-HT_1A receptor is a critical target in the treatment of depression and anxiety. Bufotenine derivatives, such as 5-methoxy-<i>N</i>,<i>N</i>-dimethyltryptamine (5-MeO-DMT), 5-hydroxy-<i>N</i>,<i>N</i>-dimethyltryptamine (5-OH-DMT), and 5-hydroxy-<i>N</i>,<i>N</i>,<i>N</i>-dimethyltryptamine-derived from traditional Chinese medicine-have shown antidepressant potential. However, the structural basis of their interaction with 5-HT_1A and their pharmacological profiles remain incompletely understood. This study investigated bufotenine derivatives acting on multiple serotonin receptors, highlighting 5-HT_1A as a key mediator of antidepressant effects while recognizing 5-HT_2A as primarily responsible for hallucinogenic outcomes, to identify candidates with therapeutic efficacy but reduced hallucinogenic liability. We determined the cryo-electron microscopy structures of 5-HT_1A bound to selected bufotenine derivatives. Functional assays in mice, including behavioral tests and receptor activation studies, were used to evaluate the antidepressant of each compound. Structural analysis revealed that all bufotenine derivatives engage conserved motifs within the 5-HT_1A binding pocket, with 5-OH-DMT displaying a distinct interaction pattern. Behavioral assays showed that 5-OH-DMT and 5-MeO-DMT retained strong antidepressant and anxiolytic effects. These pharmacological differences correlate with their unique receptor binding conformation. This study delineated the structural pharmacology of bufotenine derivatives at the 5-HT_1A receptor, identifying 5-OH-DMT and 5-MeO-DMT as promising antidepressant and anxiolytic candidates. The findings establish a molecular framework for the development of next-generation nonhallucinogenic therapeutics aimed at 5-HT_1A.