Dino Luethi1, Daniel Trachsel2, Marius C Hoener3, Matthias E Liechti4. 1. Division of Clinical Pharmacology and Toxicology, Department of Biomedicine, University Hospital Basel and University of Basel, Basel, Switzerland. 2. ReseaChem GmbH, Burgdorf, Switzerland. 3. Neuroscience Research, pRED, Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd, Basel, Switzerland. 4. Division of Clinical Pharmacology and Toxicology, Department of Biomedicine, University Hospital Basel and University of Basel, Basel, Switzerland. Electronic address: matthias.liechti@usb.ch.
Abstract
BACKGROUND: 4-Thio-substituted phenethylamines (2C-T drugs) are potent psychedelics with poorly defined pharmacological properties. Because of their psychedelic effects, 2C-T drugs are sometimes sold as new psychoactive substances (NPSs). The aim of the present study was to characterize the monoamine receptor and transporter interaction profiles of a series of 2C-T drugs. METHODS: We determined the binding affinities of 2C-T drugs at monoamine receptors and transporters in human cells that were transfected with the respective receptors or transporters. We also investigated the functional activation of serotonergic 5-hydroxytryptamine 2A (5-HT2A) and 5-HT2B receptors, activation of human trace amine-associated receptor 1 (TAAR1), and inhibition of monoamine uptake transporters. RESULTS: 2C-T drugs had high affinity for 5-HT2A and 5-HT2C receptors (1-54 nM and 40-350 nM, respectively). With activation potencies of 1-53 nM and 44-370 nM, the drugs were potent 5-HT2A receptor and 5-HT2B receptor, respectively, partial agonists. An exception to this were the benzylthiophenethylamines, which did not potently activate the 5-HT2B receptor (EC50 > 3000 nM). Furthermore, the compounds bound to serotonergic 5-HT1A and adrenergic receptors. The compounds had high affinity for the rat TAAR1 (5-68 nM) and interacted with the mouse but not human TAAR1. The 2C-T drugs did not potently interact with monoamine transporters (Ki > 4000 nM). CONCLUSION: The receptor binding profile of 2C-T drugs predicts psychedelic effects that are mediated by potent 5-HT2 receptor interactions. This article is part of the Special Issue entitled 'Designer Drugs and Legal Highs.'
BACKGROUND:4-Thio-substituted phenethylamines (2C-T drugs) are potent psychedelics with poorly defined pharmacological properties. Because of their psychedelic effects, 2C-T drugs are sometimes sold as new psychoactive substances (NPSs). The aim of the present study was to characterize the monoamine receptor and transporter interaction profiles of a series of 2C-T drugs. METHODS: We determined the binding affinities of 2C-T drugs at monoamine receptors and transporters in human cells that were transfected with the respective receptors or transporters. We also investigated the functional activation of serotonergic 5-hydroxytryptamine 2A (5-HT2A) and 5-HT2B receptors, activation of humantrace amine-associated receptor 1 (TAAR1), and inhibition of monoamine uptake transporters. RESULTS: 2C-T drugs had high affinity for 5-HT2A and 5-HT2C receptors (1-54 nM and 40-350 nM, respectively). With activation potencies of 1-53 nM and 44-370 nM, the drugs were potent 5-HT2A receptor and 5-HT2B receptor, respectively, partial agonists. An exception to this were the benzylthiophenethylamines, which did not potently activate the 5-HT2B receptor (EC50 > 3000 nM). Furthermore, the compounds bound to serotonergic 5-HT1A and adrenergic receptors. The compounds had high affinity for the ratTAAR1 (5-68 nM) and interacted with the mouse but not humanTAAR1. The 2C-T drugs did not potently interact with monoamine transporters (Ki > 4000 nM). CONCLUSION: The receptor binding profile of 2C-T drugs predicts psychedelic effects that are mediated by potent 5-HT2 receptor interactions. This article is part of the Special Issue entitled 'Designer Drugs and Legal Highs.'
Authors: Dino Luethi; Karolina E Kolaczynska; Melanie Walter; Masaki Suzuki; Kenner C Rice; Bruce E Blough; Marius C Hoener; Michael H Baumann; Matthias E Liechti Journal: J Psychopharmacol Date: 2019-04-30 Impact factor: 4.153
Authors: Esther Papaseit; Magí Farré; Clara Pérez-Mañá; Marta Torrens; Mireia Ventura; Mitona Pujadas; Rafael de la Torre; Débora González Journal: Front Pharmacol Date: 2018-03-13 Impact factor: 5.810
Authors: Karolina E Kolaczynska; Dino Luethi; Daniel Trachsel; Marius C Hoener; Matthias E Liechti Journal: Front Pharmacol Date: 2019-11-28 Impact factor: 5.810
Authors: Karolina E Kolaczynska; Dino Luethi; Daniel Trachsel; Marius C Hoener; Matthias E Liechti Journal: Front Pharmacol Date: 2022-02-09 Impact factor: 5.810