Hallucinogen chemistry guides antidepressant drug discovery
C&EN Global Enterprise – February 07, 2022
Source: OpenAlex
Summary
A breakthrough in drug discovery reveals how hallucinogen compounds like LSD and psilocybin bind to a specific serotonin receptor (5-HT 2A), causing their psychedelic effects. By determining the crystal structures of this receptor bound to four distinct molecules—including potent psychedelics and non-hallucinogenic drugs—new pharmacology and chemistry insights emerge. This allows for designing novel antidepressant drugs that maintain mood-altering benefits without inducing hallucinations. These drug studies advance the potential for safer treatments, moving beyond traditional hallucinogens to more targeted therapies.
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