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-HT1A, 5-HT2A, and 5-HT2C, adrenergic α1A and α2A, 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-HT2A and 5-HT2B receptors, and TAAR1 was examined. Generally, scalines and 3C-scalines bound with weak to moderately high affinity to the 5-HT2A receptor (K i = 150–12,000 nM). 3C-scalines showed a marginal preference for the 5-HT2A vs the 5-HT2C and 5-HT1A receptors whereas no preference was observed for the scalines. Extending the 4-alkoxy substituent increased 5-HT2A and 5-HT2C receptors binding affinities, and enhanced activation potency and efficacy at the 5-HT2A but not at the 5-HT2B receptor. Introduction of fluorinated 4-alkoxy substituents generally increased 5-HT2A and 5-HT2C receptors binding affinities and increased the activation potency and efficacy at the 5-HT2A and 5-HT2B receptors. Overall, no potent affinity was observed at non-serotonergic targets. As observed for other psychedelics, scalines and 3C-scalines interacted with the 5-HT2A and 5-HT2C receptors and bound with higher affinities (up to 63-fold and 34-fold increase, respectively) when compared to mescaline.
Highlights
IntroductionSerotonin [5-hydroxytryptamine, 5-HT (1; Figure 1)] modulates vital central nervous system processes like appetite, sexual activity, memory, attention, or sleep through interactions with various 5-HT receptors
Serotonin [5-hydroxytryptamine, 5-HT (1; Figure 1)] modulates vital central nervous system processes like appetite, sexual activity, memory, attention, or sleep through interactions with various 5-HT receptors (G protein-coupled receptors except for5-HT3 receptors) (Berger et al, 2009; Pithadia and Jain 2009).Altered 5-HT modulation can lead to several psychiatric conditions like anxiety, depression, or schizophrenia (Rapport et al, 1948)
The cell membrane preparations were obtained from Chinese hamster ovary cells, Chinese hamster lung cells and HEK 293 cells
Summary
Serotonin [5-hydroxytryptamine, 5-HT (1; Figure 1)] modulates vital central nervous system processes like appetite, sexual activity, memory, attention, or sleep through interactions with various 5-HT receptors Altered 5-HT modulation can lead to several psychiatric conditions like anxiety, depression, or schizophrenia (Rapport et al, 1948). Distributed in the central nervous system, the. Due to the lack of selectivity, identifying the various roles of each receptor subtype is difficult. In recent years, this issue has been tackled by the synthesis of selective ligands for each receptor isoform. Ligands which show high affinity-binding at the 5-HT2 receptor family but are devoid of subtype selectivity include substituted phenethylamines like
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