| Autor: |
Kolaczynska KE; Division of Clinical Pharmacology and Toxicology, Department of Biomedicine, University Hospital Basel and University of Basel, Basel, Switzerland., Luethi D; Division of Clinical Pharmacology and Toxicology, Department of Biomedicine, University Hospital Basel and University of Basel, Basel, Switzerland.; Center for Physiology and Pharmacology, Institute of Pharmacology, Medical University of Vienna, Vienna, Austria., Trachsel D; ReseaChem GmbH, Burgdorf, Switzerland., Hoener MC; Neuroscience Research, pRED, Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd, Basel, Switzerland., Liechti ME; Division of Clinical Pharmacology and Toxicology, Department of Biomedicine, University Hospital Basel and University of Basel, Basel, Switzerland. |
| Jazyk: |
angličtina |
| Zdroj: |
Frontiers in pharmacology [Front Pharmacol] 2019 Nov 28; Vol. 10, pp. 1423. Date of Electronic Publication: 2019 Nov 28 (Print Publication: 2019). |
| DOI: |
10.3389/fphar.2019.01423 |
| Abstrakt: |
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-HT 1A , 5-HT 2A , and 5-HT 2C receptors, trace amine-associated receptor 1 (TAAR1), adrenergic α 1 and α 2 receptors, dopaminergic D 2 receptor, and at monoamine transporters, using target-transfected cells. Additionally, activation of 5-HT 2A and 5-HT 2B receptors and TAAR1 was determined. Furthermore, we assessed monoamine transporter inhibition. Results: Both the phenethylamine and amphetamine derivatives ( K i = 8-1700 nM and 61-4400 nM, respectively) bound with moderate to high affinities to the 5-HT 2A receptor with preference over the 5-HT 1A and 5-HT 2C receptors (5-HT 2A /5-HT 1A = 1.4-333 and 5-HT 2A /5-HT 2C = 2.1-14, respectively). Extending the 4-alkoxy-group generally increased binding affinities at 5-HT 2A and 5-HT 2C 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-HT 2A and 5-HT 2C receptors. Little or no effect was observed at the 5-HT 1A receptor for any of the substances tested ( K i ≥ 2700 nM). Phenethylamines bound more strongly to the TAAR1 ( K i = 21-3300 nM) compared with their amphetamine analogs ( K i = 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-HT 2A/C subtype also increase, and only weak 5-HT 2A/C subtype selectivities were achieved. At least from the binding data available (i.e., high affinity binding at the 5-HT 2A receptor) one may predict mainly psychedelic-like effects in humans, at least for some of the compound investigated herein.
(Copyright © 2019 Kolaczynska, Luethi, Trachsel, Hoener and Liechti.) |
| Databáze: |
MEDLINE |
| Externí odkaz: |
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