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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 targets; in vitro; . Binding affinity at human serotonergic 5-HT; 1A; , 5-HT; 2A; , and 5-HT; 2C; , adrenergic α; 1A; and α; 2A; , and dopaminergic D; 2; 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.
