Towards “unmakable” psychedelics: SAR exploration of psilocin analogs obtained by a HATU-mediated amide coupling strategy

Stirn J, Berger R, Hübner H, Gmeiner P, Klein CD (2025)

Publication Type: Journal article

Publication year: 2025

Book Volume: 15

Article Number: 100278

DOI: 10.1016/j.ejmcr.2025.100278

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 N1-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-HT1/2A). An increase in steric bulk at the aliphatic nitrogen appears to be detrimental to the affinity to the 5-HT2A receptor, whereas azetidinyl tryptamines bearing a terminal aryl moiety demonstrated remarkably high affinity.

Authors with CRIS profile

Harald Hübner Lehrstuhl für Pharmazeutische Chemie Peter Gmeiner Lehrstuhl für Pharmazeutische Chemie

Additional Organisation(s)

FAU Forschungszentrum Neue Wirkstoffe (FAU NeW)

Involved external institutions

Ruprecht-Karls-Universität Heidelberg DE Germany (DE)

How to cite

APA:

Stirn, J., Berger, R., Hübner, H., Gmeiner, P., & Klein, C.D. (2025). Towards “unmakable” psychedelics: SAR exploration of psilocin analogs obtained by a HATU-mediated amide coupling strategy. , 15. https://doi.org/10.1016/j.ejmcr.2025.100278

MLA:

Stirn, Judith, et al. "Towards “unmakable” psychedelics: SAR exploration of psilocin analogs obtained by a HATU-mediated amide coupling strategy." 15 (2025).

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