Serotonin receptors are targets for drugs treating depression, obesity, and migraine headaches. Crystal structures of two serotonin receptor subtypes bound to antimigraine medications or a precursor of LSD reveal how subtle differences in ligand binding cause substantial differences in receptor signaling and biological responses. The structures show that the same ligand can activate one or both of the two main serotonin receptor signaling mechanisms, depending on which receptor it binds.
Two research teams independently determined the crystal structures of two serotonin receptors bound to antimigraine drugs or a precursor of LSD. The structures show that subtle differences in how ligands bind to these receptors lead to substantial differences in the signals generated and the resulting biological responses. The same ligand can activate one or both of the two main serotonin receptor signaling mechanisms, depending on which specific receptor it binds to.
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.