How Light Rewires Amino Acids into Serotonin Receptor Ligands

Indole functionalization remains one of the central challenges in synthetic and medicinal chemistry, particularly at the C4 position, which is difficult to access using conventional methods. At the same time, tryptamine-based scaffolds are core motifs in many bioactive molecules, including ligands of the serotonin 5-HT2A receptor. Traditional synthetic routes to constrained tryptamine analogues are often step-intensive, poorly selective, and limited in structural diversity. There is a growing need for concise, modular strategies that can directly convert simple building blocks into complex, pharmacologically relevant architectures.

The study demonstrates that light can be used not only to initiate radical chemistry but to unlock otherwise inaccessible regioselectivity in indole functionalization. By converting readily available amino acids into complex, bioactive tryptamine-like scaffolds in a short sequence, the work bridges synthetic photochemistry and medicinal chemistry. Importantly, the resulting compounds show activity at the 5-HT2A receptor, highlighting a direct path from photochemical reactivity to biologically relevant function.

The photochemical transformation relies on ultraviolet irradiation, which may limit scalability and functional group compatibility compared to visible-light photoredox systems. The scope is focused on indole-containing substrates, and the generality of the approach toward other heteroaromatic systems remains unexplored. While biological activity is demonstrated, further optimization would be required to assess selectivity, metabolic stability, and therapeutic potential of the resulting compounds.