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Transforming Amino Acids into Serotonin 5-HT2A Receptor Ligands Using Photochemistry. J Am Chem Soc 2025 Dec 31;147(52):48400-48415

Date

12/16/2025

Pubmed ID

41400162

Pubmed Central ID

PMC13185789

DOI

10.1021/jacs.5c19817

Scopus ID

2-s2.0-105026446853 (requires institutional sign-in at Scopus site)

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-HT2A receptor was investigated both in silico and in vitro. These azocinoindoles show both full and partial agonist 5-HT2A Gq activation efficacies and suppress the head-twitch response in vivo, suggesting they belong to an emerging class of nonhallucinogenic 5-HT2A agonists. The azocinoindole core and the synthetic advances described here that enable its structural diversification provide a valuable platform for serotonin receptor drug discovery.

Author List

Beckett JOS, Buzdygon R, Nguyen S, Clark AA, Schalk SS, Svanholm LEH, Brasher TJ, Bazin M, Cuccurazzu B, Halberstadt AL, McCorvy JD, Mascal M

Author

John McCorvy PhD Associate Professor in the Cell Biology Neurobiology and Anatomy department at Medical College of Wisconsin




MESH terms used to index this publication - Major topics in bold

Amino Acids
Humans
Indoles
Ligands
Molecular Structure
Photochemical Processes
Receptor, Serotonin, 5-HT2A
Serotonin 5-HT2 Receptor Agonists
Tryptamines