3,4,5-Trimethoxyphenethylamine (mescaline) is a psychedelic alkaloid found in peyote cactus. Related 4-alkoxy-3,5-dimethoxy-substituted phenethylamines (scalines) and amphetamines (3C-scalines) are reported to induce similarly potent psychedelic effects and are therefore potential novel therapeutics for psychedelic-assisted therapy. Herein, several pharmacologically uninvestigated scalines and 3C-scalines were examined at key monoamine targetsin vitro. Binding affinity at human serotonergic 5-HT_1A, 5-HT_2A, and 5-HT_2C, adrenergic α_1A and α_2A, and dopaminergic D₂ receptors, rat and mouse trace amine-associated receptor 1 (TAAR1), and human monoamine transporters were assessed using target specific transfected cells. Furthermore, activation of human 5-HT_2A and 5-HT_2B receptors, and TAAR1 was examined. Generally, scalines and 3C-scalines bound with weak to moderately high affinity to the 5-HT_2A receptor (K_i = 150-12,000 nM). 3C-scalines showed a marginal preference for the 5-HT_2A vs the 5-HT_2C and 5-HT_1A receptors whereas no preference was observed for the scalines. Extending the 4-alkoxy substituent increased 5-HT_2A and 5-HT_2C receptors binding affinities, and enhanced activation potency and efficacy at the 5-HT_2A but not at the 5-HT_2B receptor. Introduction of fluorinated 4-alkoxy substituents generally increased 5-HT_2A and 5-HT_2C receptors binding affinities and increased the activation potency and efficacy at the 5-HT_2A and 5-HT_2B receptors. Overall, no potent affinity was observed at non-serotonergic targets. As observed for other psychedelics, scalines and 3C-scalines interacted with the 5-HT_2A and 5-HT_2C receptors and bound with higher affinities (up to 63-fold and 34-fold increase, respectively) when compared to mescaline.

DT is an employee of ReseaChem GmbH and MH is an employee of F. Hoffmann-La Roche. ML is a consultant for Mind Medicine, Inc. Knowhow associated with these substances investigated in this work is owned by Mind Medicine, Inc. Mind Medicine, Inc. had no role in financing, planning, or conducting the present research or the present publication. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.