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.
A new chemical method enables the creation of acyloxymethyl (ACOM) prodrugs of tryptamines, including the psychedelic psilocin and the anti-migraine drug sumatriptan, by selectively protecting the indole nitrogen with a carbamate group. This approach overcomes previous chemoselectivity problems. In vitro tests show that the rate of bioactivation in human plasma can be tuned by altering the acyl residue, with half-lives up to 240 minutes. However, rapid breakdown in human saliva likely prevents sublingual or buccal delivery, though other routes like oral, transdermal, nasal, or intravenous administration remain possible.