Structure-based discovery of nonhallucinogenic psychedelic analogs

Area of Science:

• Neuroscience
• Pharmacology
• Structural Biology

Background:

• Drugs targeting the serotonin 2A receptor (5-HT_2AR) are crucial for neuropsychiatric treatments but often cause hallucinations.
• Understanding the molecular interactions of these drugs with 5-HT_2AR is key to developing safer alternatives.

Purpose of the Study:

• To elucidate the structural basis of psychedelic drug binding to the 5-HT_2AR.
• To leverage structural insights for the rational design of nonhallucinogenic 5-HT_2AR-targeting therapeutics.

Main Methods:

• X-ray crystallography was used to determine the structures of 5-HT_2AR in complex with psilocin, LSD, serotonin, and lisuride.
• Structure-based drug design principles were applied to develop novel 5-HT_2AR agonists.
• Antidepressant-like activity and hallucinogenic potential were assessed in preclinical models.

Main Results:

• Identified a second, non-canonical binding mode for serotonin and psilocin within the 5-HT_2AR.
• Designed and synthesized IHCH-7113 and other β-arrestin-biased 5-HT_2AR agonists.
• Demonstrated antidepressant-like effects in mice without observed hallucinogenic properties.

Conclusions:

• The determined 5-HT_2AR complex structures provide critical insights into drug-receptor interactions.
• This work facilitates the structure-based design of novel, nonhallucinogenic psychedelic analogs for therapeutic applications.
• The findings pave the way for developing safer treatments for neuropsychiatric disorders.