Transforming Amino Acids into Serotonin 5-HT 2A Receptor Ligands Using Photochemistry

A new chemical method uses light to trigger a cyclization reaction that attaches a functional group to the fourth carbon of the indole ring, enabling the efficient synthesis of ring-constrained tryptamine analogs. Amino acids were linked to tryptamine and exposed to UV light to produce lactams bridging specific positions on the indole structure. The resulting reduced lactams, called azocinoindoles, were tested for activity at the serotonin 5-HT2A receptor. In computer models and lab experiments, these compounds acted as full or partial activators of the receptor's Gq signaling pathway. In mice, they suppressed the head-twitch response, a behavior linked to hallucinogenic effects, suggesting these compounds are nonhallucinogenic 5-HT2A agonists.

Study at a glance

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.