Towards "unmakable" psychedelics: SAR exploration of psilocin analogs obtained by a HATU-mediated amide coupling strategy
Judith Stirn, Raphael Berger, Harald Hübner, Peter Gmeiner, Christian D. Klein
European Journal of Medicinal Chemistry Reports June 3, 2025 DOI: 10.1016/j.ejmcr.2025.100278 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Experimental study Peer reviewed |
|---|---|
| Topics | Psilocybin |
| Citations | 1 |
| Key findings | Increasing steric bulk at the aliphatic nitrogen reduces affinity for the 5-HT2A receptor, whereas azetidinyl tryptamines bearing a terminal aryl moiety show remarkably high affinity. |
Abstract
4-Hydroxytryptamines such as psilocin and its prodrug psilocybin are of considerable current interest for innovative antidepressant and other neuropsychiatric treatments. We here present a synthetic route towards 4-hydroxytryptamines displaying a high versatility for SAR exploration at the aliphatic nitrogen. The core concept is to apply HATU-mediated amide couplings to a readily accessible and stable N 1 -Boc-indole-3-glyoxylic acid precursor followed by N -deprotection under mild conditions. We illustrate the versatility of this approach by the synthesis of various sterically hindered, conformationally constrained, chiral, and electron-deficient 4-hydroxytryptamines, including closely related congeners of iprocin. In addition, the structure-activity relationships of the obtained compounds are explored with a focus on their interaction with the serotonin receptors 1A and 2A (5-HT 1/2A ). An increase in steric bulk at the aliphatic nitrogen appears to be detrimental to the affinity to the 5-HT 2A receptor, whereas azetidinyl tryptamines bearing a terminal aryl moiety demonstrated remarkably high affinity.
Comparable studies
Other experimental studies on psilocybin, most cited first.
| Study | Year | Design | Participants |
|---|---|---|---|
| Psilocybin induces schizophrenia-like psychosis in humans via a serotonin-2 agonist action Healthy human volunteers | 1998 | Experimental study | |
| Validation of the revised Mystical Experience Questionnaire in experimental sessions with psilocybin Participants in controlled laboratory experiments receiving a moderate to high oral... | 2015 | Validation study using pooled data from five laboratory experiments | n = 184 |
| Broadband Cortical Desynchronization Underlies the Human Psychedelic State Healthy human participants | 2013 | Experimental study | |
| Long-term follow-up of psilocybin-assisted psychotherapy for psychiatric and existential distress in patients with life-threatening cancer Participants with cancer-related psychiatric distress who completed a parent randomized... | 2020 | Long-term within-subjects follow-up analysis | n = 15 |
| Enzymatic Synthesis of Psilocybin | 2017 | Laboratory study |
Citations in the library
Cites 28
- Psilocybin induces schizophrenia-like psychosis in humans via a serotonin-2 agonist action Neuroreport December 1, 1998
- Quality of Acute Psychedelic Experience Predicts Therapeutic Efficacy of Psilocybin for Treatment-Resistant Depression Frontiers in Pharmacology January 17, 2018
- Psychedelic effects of psilocybin correlate with serotonin 2A receptor occupancy and plasma psilocin levels Neuropsychopharmacology January 26, 2019
- Crystal structure of an LSD-bound human serotonin receptor Cell January 26, 2017
- Psychedelics promote plasticity by directly binding to BDNF receptor TrkB Nature Neuroscience June 1, 2023
and 23 more in the library