Receptor Interaction Profiles of 4-Alkoxy-3,5-Dimethoxy-Phenethylamines (Mescaline Derivatives) and Related Amphetamines

Abstract

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 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.

Keywords: 3C-scalines; fluorination; mescaline; phenethylamine; psychedelic; scalines.

FIGURE 1

Chemical structures of the neurotransmitter serotonin (5-HT; 1) and the psychedelics 4-bromo-2,5-dimethoxyamphetamine (DOB; 2), lysergic acid diethylamide (LSD; 3), psilocybin (4), 3,4,5-trimethoxyphenethylamine (mescaline; 5), 3,4,5-trimethoxyamphetamine (TMA; 6), and 2,5-dimethoxy-4-methyl-amphetamine (DOM; 7), and the core structure of the 4-alkoxy-3,5-dimethoxyphenethylamines (scalines; 8) and 4-alkoxy-3,5-dimethoxyamphetamine (3C-scalines; 9).

FIGURE 2

Chemical structures of various previously investigated scalines and 3C-scalines (Shulgin and Shulgin 1991; Shulgin and Shulgin 1997; Trachsel et al., 2013). Human oral doses and duration of action were taken from (Shulgin and Shulgin 1991; Shulgin and Shulgin 1997; Trachsel et al., 2013). Compounds tested in vitro in the present investigation are underlined.