Hallucinogen chemistry guides antidepressant drug discovery

A structural biology approach reveals how hallucinogenic and nonhallucinogenic molecules bind to the 5-HT 2A serotonin receptor, a target for LSD and psilocybin that also treats mood disorders. By determining crystal structures of the receptor bound to LSD, psilocin, serotonin, or lisuride, researchers visualized differences in binding and designed molecules that may retain mood-altering effects without causing hallucinations.

Study at a glance

Abstract

Scientists have long sought the secrets of the 5-HT 2A serotonin receptor—a central nervous system receptor that binds hallucinogenic compounds, including LSD and psilocybin. Many hope to discover why these molecules cause hallucinations when they bind to 5-HT 2A while other compounds that bind to the receptor, including serotonin, do not. LSD and psilocybin have been shown to treat mood disorders such as depression, and scientists wonder if they can design molecules that maintain that mood-altering ability without causing hallucinations. Researchers now report a structural biology–guided strategy for making such molecules. A team led by Sheng Wang of the Chinese Academy of Sciences and Jianjun Cheng of ShanghaiTech University determined the crystal structures of the 5-HT 2A receptor bound to LSD, psilocin (the active form of psilocybin), serotonin, or lisuride, a nonhallucinogenic treatment for Parkinson's disease . After visualizing the differences in how those molecules bind, the researchers then designed