Phenethylaminylation: Preliminary In Vitro Evidence for the Covalent Transamidation of Psychedelic Phenethylamines to Glial Proteins using 3,5-Dimethoxy-4-(2-Propynyloxy)-Phenethylamine as a Model Compound

Psychedelics are well known for their ability to produce profoundly altered states of consciousness. But, more importantly, the effects of psychedelics can influence neurobehavioral changes that last well after these acute subjective effects end. This phenomenon is currently being leveraged in the development of psychedelic-assisted psychotherapies for the treatment of multiple neuropsychiatric disorders. The cellular and molecular mechanisms by which single doses of psychedelics are able to mediate long-term cognitive changes are an active area of research. We hypothesize that psychedelics contribute to long term changes in cellular state by covalently modifying proteins. This post-translational modification by psychedelics is possible through the transglutaminase-mediated transamidation of their amine termini to glutamine carboxamide residues. Here, we synthesize and utilize a propargylated analogue of mescaline - the classic serotonergic psychedelic phenethylamine found in cacti species - to identify putative protein targets of psychedelic modifications through the use of click-chemistry in a primary human astrocyte cell culture model. Our preliminary findings indicate that a diverse array of glial proteins may be substrates for transglutaminase 2-mediated monoaminylation by our model phenethylamine ("phenethylaminylation"). Based on these points, we speculatively highlight new directions for the study of this putative noncanonical psychedelic activity.