Discovery of Highly Selective 5-HT_2A Agonists Using Structure-Guided Design

Area of Science:

• Neuroscience and Pharmacology
• Medicinal Chemistry

Background:

• Growing interest in psychedelics as neuroplastic therapies necessitates tools to study their mechanisms.
• Developing selective serotonin 5-HT_2A receptor agonists is crucial for understanding psychedelic effects.

Purpose of the Study:

• To design and validate highly selective 5-HT_2A receptor agonists.
• To investigate structure-activity relationships for enhancing 5-HT_2A target engagement.

Main Methods:

• Structure-based drug design targeting residue L123^2.53 in the 5-HT_2A receptor.
• Synthesis and characterization of novel N-benzyl scaffold compounds.
• In vitro and in vivo assays including receptor binding, RNA editing isoform analysis, mutant receptor studies, ortholog testing, and mouse head-twitch response.

Main Results:

• Achieved high selectivity for 5-HT_2A over 5-HT_2C by increasing steric bulk on the N-benzyl scaffold.
• Comprehensive validation of selectivity across various assays and species orthologs.
• Demonstrated rational design principles for optimizing 5-HT_2A agonist target engagement.

Conclusions:

• Highly selective 5-HT_2A agonists can be rationally designed using structure-based approaches.
• These novel compounds provide valuable tools for advancing the neurobiological study of psychedelics and their therapeutic potential.