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Front. Pharmacol. | doi: 10.3389/fphar.2019.01423

Receptor interaction profiles of 4-alkoxy-substituted 2,5-dimethoxyphenethylamines and related amphetamines.

  • 1Department of Clinical Pharmacology and Toxicology, University Hospital of Basel, Switzerland
  • 2Center for Physiology and Pharmacology, Medical University of Vienna, Austria
  • 3ReseaChem GmbH, Switzerland
  • 4Roche Innovation Center Zurich, Switzerland

Background: 2,4,5-Trimethoxyamphetamine (TMA-2) is a potent psychedelic compound. Structurally related 4-alkyloxy-substituted 2,5-dimethoxyamphetamines and phenethylamine congeners (2C-O derivatives) have been described but their pharmacology is mostly undefined. Therefore, we examined receptor binding and activation profiles of these derivatives at monoamine receptors and transporters.
Methods: Receptor binding affinities were determined at the serotonergic 5-HT1A, 5-HT2A, and 5-HT2C receptors, trace amine-associated receptor 1 (TAAR1), adrenergic α1 and α2 receptors, dopaminergic D2 receptor, and at monoamine transporters, using target-transfected cells. Additionally, activation of 5-HT2A and 5-HT2B receptors and TAAR1 was determined. Furthermore, we assessed monoamine transporter inhibition.
Results: Both the phenethylamine and amphetamine derivatives (Ki = 8–1700 nM and 61–4400 nM, respectively) bound with moderate to high affinities to the 5-HT2A receptor with preference over the 5-HT1A and 5-HT2C receptors (5-HT2A/5-HT1A=1.4–333 and 5-HT2A/5-HT2C = 2.1–14, respectively). Extending the 4-alkoxy-group generally increased binding affinities at 5-HT2A and 5-HT2C receptors but showed mixed effects in terms of activation potency and efficacy at these receptors. Introduction of a terminal fluorine atom into the 4-ethoxy substituent by trend decreased, and with progressive fluorination increased affinities at the 5-HT2A and 5-HT2C receptors. Little or no effect was observed at the 5-HT1A receptor for any of the substances tested (Ki ≥ 2700 nM). Phenethylamines bound more strongly to the TAAR1 (Ki = 21–3300 nM) compared with their amphetamine analogs (Ki = 630–3100 nM).
Conclusion: As seen with earlier series investigated, the 4-alkyloxy-substituted 2,5-dimethoxyamphetamines and phenethylamines share some trends with the many other phenethylamine pharmacophore containing compounds, such as when increasing the size of the 4-substituent and increasing the lipophilicity, the affinities at the 5-HT2A/C subtype also increase, and only weak 5-HT2A/C subtype selectivities were achieved. At least from the binding data available (i.e., high affinity binding at the 5-HT2A receptor) one may predict mainly psychedelic-like effects in humans, at least for some of the compound investigated herein.

Keywords: TMA-2, Phenethylamine, 2C-O, 3C-O, receptor, transporter, psychedelic

Received: 25 Jul 2019; Accepted: 07 Nov 2019.

Copyright: © 2019 Kolaczynska, Luethi, Trachsel, Hoener and Liechti. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

* Correspondence: Prof. Matthias E. Liechti, Department of Clinical Pharmacology and Toxicology, University Hospital of Basel, Basel, Switzerland,