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

Karolina E. Kolaczynska, Dino Luethi, Dino Luethi, Daniel Trachsel, Marius C. Hoener, Matthias E. Liechti

Frontiers in Pharmacology February 9, 2022 DOI: 10.3389/fphar.2021.794254 (opens in new tab)

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Study at a glance

AI-extracted from the abstract
Characteristics In vitro study Peer reviewed
Population Transfected cells expressing 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
Topics Mescaline
Keywords Phenethylamine 3c-scalines Fluorination Synthetic psychedelics Neuropharmacology Medicinal chemistry Drug discovery
Citations 16
Key points Scalines and 3C-scalines bind to 5-HT2A and 5-HT2C receptors with higher affinities than mescaline, with fluorinated 4-alkoxy substituents generally increasing binding affinities and activation potency at these receptors.

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 (Ki = 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.

Comparable studies

Other preclinical and animal studies on mescaline, most cited first.

Study Year Design Participants
Correlation between the potency of hallucinogens in the mouse head-twitch response assay and their behavioral and subjective effects in other species. C57BL/6J mice 2020 Experimental study with dose-response experiments
Brain mechanisms of hallucinogens and entactogens Humans and rats 2001 Review
Effects of hallucinogenic agents mescaline and phencyclidine on zebrafish behavior and physiology Zebrafish (Danio rerio) 2012 Experimental study
Lysergic Acid Diethylamide- and Mescaline-Induced Attenuation of the Effect of Punishment in the Rat Rats 1976 Experimental study
Dihydrobenzofuran Analogues of Hallucinogens. 3. Models of 4-Substituted (2,5-Dimethoxyphenyl)alkylamine Derivatives with Rigidified Methoxy Groups Rats (trained to discriminate saline from LSD tartrate) and rat cortical and... 1996 In vivo drug discrimination assay and in vitro radioligand binding assay

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Mescaline Psychedelic-assisted therapy Serotonin