Towards "unmakable" psychedelics: SAR exploration of psilocin analogs obtained by a HATU-mediated amide coupling strategy
European Journal of Medicinal Chemistry Reports June 3, 2025 Judith Stirn, Raphael Berger, Harald Hübner et al. 1 citation
A new synthetic method produces 4-hydroxytryptamines (the chemical family that includes psilocin and psilocybin) with high versatility for exploring how changes to the nitrogen atom affect biological activity. The approach uses a stable precursor and mild conditions to create sterically hindered, chiral, and electron-deficient variants, including close relatives of iprocin. Testing these compounds on serotonin receptors 1A and 2A revealed that adding bulkier groups to the nitrogen lowers affinity for the 5-HT2A receptor, while azetidinyl tryptamines with a terminal aryl group show remarkably high affinity.