Transforming Amino Acids into Serotonin 5-HT 2A Receptor Ligands Using Photochemistry
J.O.S. Beckett, Ryan Buzdygon, Steven Nguyen, A. Clark, Serena S. Schalk, Lena Elisabeth H. Svanholm, Trey Brasher, M. Bazin, Bruna Cuccurazzu, Adam L. Halberstadt, John D. Mccorvy, Mark Mascal
Journal of the American Chemical Society December 16, 2025 DOI: 10.1021/jacs.5c19817 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Method development with in silico and in vitro pharmacological testing Peer reviewed |
|---|---|
| Topics | Serotonin |
| Keywords | Indole test Agonist Tryptophan Tryptamines Combinatorial chemistry Stereochemistry Amino acid 5-HT Receptor Ring chemistry |
| Citations | 1 |
| Key points | Azocinoindoles act as full and partial 5-HT2A Gq agonists and suppress the head-twitch response in vivo, indicating they are nonhallucinogenic 5-HT2A agonists. |
Abstract
A light-induced cyclization via a radical spin-center shift process that results in the direct functionalization of the indole ring at the C4-position is developed into a practical method for the synthesis of medicinally active, ring-constrained tryptamine analogs. Amino acids were coupled to tryptamine and irradiated with UV light to produce a library of lactams bridging the C3- and C4-positions of the indole nucleus. An extension to this method is introduced that employs α-acetoxy- and α-lactone-substituted tryptamides. Using optimized conditions and these easily accessed precursors, C3- to C4-bridged indoles can now be produced in good to excellent yields, free of the C2-regioisomers that are often seen using α-halo tryptamide substrates. Due to the structural similarities of the reduced lactams (azocinoindoles) with known psychoactive tryptamines, their functional activation at the serotonin 5-HT 2A receptor was investigated both in silico and in vitro . These azocinoindoles show both full and partial agonist 5-HT 2A Gq activation efficacies and suppress the head-twitch response in vivo, suggesting they belong to an emerging class of nonhallucinogenic 5-HT 2A agonists. The azocinoindole core and the synthetic advances described here that enable its structural diversification provide a valuable platform for serotonin receptor drug discovery.