Structural Pharmacology of Bufotenine Derivatives in Activating the 5-HT 1A Receptor for Therapeutic Potential in Depression and Anxiety
Research January 1, 2025 Shujie Li, Shu-Jie Li, Qingning Yuan et al.
Bufotenine derivatives from traditional Chinese medicine, including 5-MeO-DMT and 5-OH-DMT, show promise as antidepressants and anxiolytics with reduced hallucinogenic effects. Cryo-electron microscopy revealed how these compounds bind to the 5-HT1A receptor, a key target for depression and anxiety treatment, while avoiding strong activation of the 5-HT2A receptor linked to hallucinations. Behavioral tests in mice confirmed that 5-OH-DMT and 5-MeO-DMT retain strong antidepressant and anxiety-reducing effects. The distinct binding conformation of 5-OH-DMT correlates with its pharmacological profile. These findings provide a molecular basis for developing nonhallucinogenic drugs targeting the 5-HT1A receptor.