Receptor Interaction Profiles of 4-Alkoxy-Substituted 2,5-Dimethoxyphenethylamines and Related Amphetamines

Kolaczynska, Karolina E. and Luethi, Dino and Trachsel, Daniel and Hoener, Marius C. and Liechti, Matthias E.. (2019) Receptor Interaction Profiles of 4-Alkoxy-Substituted 2,5-Dimethoxyphenethylamines and Related Amphetamines. Frontiers in Pharmacology, 10. p. 1423.

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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.
Faculties and Departments:03 Faculty of Medicine > Bereich Medizinische Fächer (Klinik) > Klinische Pharmakologie
03 Faculty of Medicine > Departement Klinische Forschung > Bereich Medizinische Fächer (Klinik) > Klinische Pharmakologie
03 Faculty of Medicine > Departement Biomedizin > Department of Biomedicine, University Hospital Basel > Psychopharmacology Research (Liechti)
05 Faculty of Science > Departement Pharmazeutische Wissenschaften > Pharmazie > Molecular and Systems Toxicology (Odermatt)
UniBasel Contributors:Liechti, Matthias Emanuel
Item Type:Article, refereed
Article Subtype:Research Article
Publisher:Frontiers Media
Note:Publication type according to Uni Basel Research Database: Journal article
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Last Modified:06 Oct 2021 15:43
Deposited On:06 Oct 2021 15:43

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