Neuropharmacology
May 15, 2018
Dino Luethi, Daniel Trachsel, Marius C Hoener et al.
50 citations
4-Thio-substituted phenethylamines (2C-T drugs) are potent psychedelics with poorly defined pharmacological properties. The study characterized their interactions with monoamine receptors and transporters. 2C-T drugs showed high affinity for 5-HT2A and 5-HT2C receptors (1-54 nM and 40-350 nM, respectively) and acted as potent partial agonists at 5-HT2A and 5-HT2B receptors, except benzylthiophenethylamines which did not potently activate 5-HT2B (EC50 > 3000 nM). They also bound to 5-HT1A and adrenergic receptors and interacted with rat but not human TAAR1, but did not potently affect monoamine transporters (Ki > 4000 nM). The receptor binding profile predicts psychedelic effects mediated by potent 5-HT2 receptor interactions.
Drug Testing and Analysis
February 28, 2012
Daniel Trachsel
32 citations
Psychedelic phenethylamines range from natural mescaline to synthetic amphetamine analogues. Fluorine, widely used in medicinal chemistry, can greatly alter the psychoactivity of these compounds. An overview of over 60 fluorinated phenethylamines shows that adding fluorine may either reduce or enhance effects. For example, fluoroescaline is almost inactive, while difluoroescaline retains activity and trifluoroescaline increases potency compared to escaline. Difluoromescaline and trifluoromescaline surpass mescaline in both potency and duration.
Frontiers in Pharmacology
November 28, 2019
Karolina E. Kolaczynska, Dino Luethi, Daniel Trachsel et al.
24 citations
A series of 4-alkyloxy-substituted 2,5-dimethoxyamphetamines and their phenethylamine congeners (2C-O derivatives) were tested for binding and activation at serotonin, adrenergic, dopamine, and trace amine receptors, as well as monoamine transporters. Both amphetamine and phenethylamine derivatives bound with moderate to high affinity to the 5-HT2A receptor, with preference over 5-HT1A and 5-HT2C receptors. Extending the 4-alkoxy group generally increased binding affinities at 5-HT2A and 5-HT2C receptors but had mixed effects on activation. Phenethylamines bound more strongly to TAAR1 than their amphetamine analogs. The authors suggest that, based on high 5-HT2A binding, some compounds may produce psychedelic-like effects in humans.
Frontiers in Pharmacology
February 9, 2022
Karolina E. Kolaczynska, Dino Luethi, Dino Luethi et al.
16 citations
Mescaline, a psychedelic found in peyote, belongs to a class of compounds called scalines and 3C-scalines, which may serve as novel therapeutics for psychedelic-assisted therapy. This in vitro study examined several previously uninvestigated scalines and 3C-scalines at key monoamine targets. These compounds bound to the 5-HT2A receptor with weak to moderately high affinity (Ki = 150–12,000 nM). 3C-scalines showed a marginal preference for 5-HT2A over 5-HT2C and 5-HT1A receptors, while scalines showed no preference. Extending the 4-alkoxy substituent increased binding affinities and activation potency at 5-HT2A but not 5-HT2B receptors.
Psychopharmacology
December 7, 2022
Adam L. Halberstadt, Dino Luethi, Marius C. Hoener et al.
7 citations
A series of 4-thio-substituted phenylalkylamines, including the psychedelic drugs 2C-T-2 and 2C-T-7, were tested in mice using the head twitch response (HTR), a behavioral proxy for human psychedelic effects. Adding an α-methyl group to the parent compound 2C-T increased potency fivefold, and extending the 4-methylthio group by one to three methylene units also increased potency. Fluorination of the 4-position alkylthio chain or a 4-allylthio substituent reduced activity, and bulky 4-benzylthio groups showed little or no effect. Binding studies confirmed nanomolar affinity for 5-HT2 receptor subtypes and partial agonism at 5-HT2A, supporting classification of these compounds as psychedelic drugs.
European Neuropsychopharmacology
April 1, 2022
Karolina E. Kolaczynska, Paula Ducret, Daniel Trachsel et al.
7 citations
MDA and related amphetamine-based compounds found in street drugs and sport supplements vary in their effects on monoamine transporters and receptors. Most compounds inhibited norepinephrine uptake most potently and preferentially blocked serotonin over dopamine uptake, except 3C-BOH and N,α-DEPEA, which favored dopamine uptake. Several compounds triggered monoamine release, and most bound to serotonin 5-HT2A and 5-HT2C receptors with micromolar affinity, acting as partial or full agonists at 5-HT2A and 5-HT2B. Some also interacted with adrenergic receptors and TAAR1. Fluorinated MDA analogs resembled MDMA's profile, while 3C-BOH and N,α-DEPEA showed amphetamine-like dopaminergic activity. Further pharmacokinetic and pharmacodynamic studies are needed to assess risks and therapeutic potential.
Frontiers in Pharmacology
November 20, 2025
Karolina E. Kolaczynska, Daniel Trachsel, Marius C. Hoener et al.
1 citation
A class of psychedelic compounds called 4-substituted 2,6-dimethoxyphenethylamines and their amphetamine counterparts (Ψ derivatives) were tested for their interactions with monoamine receptors and transporters. These derivatives showed moderate to high affinity and activity at the human 5-HT2A receptor, the primary target for psychedelics, with binding affinities ranging from 8 to 1,600 nM and activation potencies from 32 to 3,400 nM. They acted as partial agonists at this receptor. The phenethylamine derivatives also bound to 5-HT1A and 5-HT2C receptors with moderate affinity, while amphetamine derivatives had weaker affinities. Some Ψ derivatives interacted with TAAR1 and adrenergic receptors. Compared to 2,4,5-trisubstituted derivatives, the 2,4,6-trisubstituted Ψ derivatives were generally less potent at the 5-HT2A receptor but more potent than 3,4,5-trisubstituted derivatives.