Transforming Amino Acids into Serotonin 5-HT 2A Receptor Ligands Using Photochemistry
Journal of the American Chemical Society December 16, 2025 J.O.S. Beckett, Ryan Buzdygon, Steven Nguyen et al. 1 citation
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.