Image_1_Receptor Interaction Profiles of 4-Alkoxy-Substituted 2,5-Dimethoxyphenethylamines and Related Amphetamines.tiff

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 α₁ and α₂ receptors, dopaminergic D₂ 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.