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

Abstract

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 (K i = 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 (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-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.

Designer drugs: mechanism of action and adverse effects

“…Consistent with the in vitro findings, psychedelic phenethylamines were shown to induce 5-HT 2A -dependent behaviors in vivo, such as wet dog shakes, back muscle contractions, and a head twitch response (Elmore et al 2018;Fantegrossi et al 2005;Halberstadt et al 2020;Halberstadt and Geyer 2014). In addition to interactions with serotonergic receptors, phenethylamine psychedelics have been shown to interact with other monoaminergic targets, including adrenergic, dopaminergic, and histaminergic receptors, monoamine transporters, and MAOs (Eshleman et al 2018;Kolaczynska et al 2019;Luethi et al 2018d;Noble et al 2018;Rickli et al 2015c;Wagmann et al 2019a). However, most of these interactions are weak compared with the potent interactions with serotonergic receptors.…”

“…At 5-HT 2A receptors, 2C and NBOMe derivatives were shown to be partial or full agonists, depending on the functional in vitro assay (Eshleman et al 2014(Eshleman et al , 2018Jensen et al 2017;Kolaczynska et al 2019;Luethi et al 2018dLuethi et al , 2019cMoya et al 2007;Rickli et al 2015c). NBOMe derivatives and most 2C derivatives have been shown to be partial agonists at 5-HT 2B receptors (Eshleman et al 2018;Jensen et al 2017;Kolaczynska et al 2019;Luethi et al 2018d;Rickli et al 2015c). At 5-HT 2C receptors, 2C derivatives were shown to be partial or full agonists (Eshleman et al 2014;Moya et al 2007), and NBOMe derivatives were shown to be full agonists (Eshleman et al 2018;Jensen et al 2017).…”

“…Similar to other psychedelics, substituted phenethylamines mainly interact with serotonergic receptors, with the highest affinity for 5-HT 2A receptors (Eshleman et al 2018;Kolaczynska et al 2019;Luethi et al 2018d;Rickli Fig. 8 Correlation between reported clinical potencies and in vitro human 5-HT 2A receptor affinities of a variety of psychedelics.…”

“…NBOMe derivatives have higher affinity for 5-HT 2A and 5-HT 2C receptors and lower affinity for 5-HT 1A receptors compared with their 2C analogs (Rickli et al 2015c). At 5-HT 2A receptors, 2C and NBOMe derivatives were shown to be partial or full agonists, depending on the functional in vitro assay (Eshleman et al 2014(Eshleman et al , 2018Jensen et al 2017;Kolaczynska et al 2019;Luethi et al 2018dLuethi et al , 2019cMoya et al 2007;Rickli et al 2015c). NBOMe derivatives and most 2C derivatives have been shown to be partial agonists at 5-HT 2B receptors (Eshleman et al 2018;Jensen et al 2017;Kolaczynska et al 2019;Luethi et al 2018d;Rickli et al 2015c).…”

New psychoactive substances: a review and updates

“…Phenethylamine derivatives interact mainly with cortical serotonin receptors, with the highest affinity for 5-HT2A receptors. 136 NBOMe derivatives have higher affinity for 5-HT2A and 5-HT2C receptors and lower affinity for 5-HT1A receptors compared with their 2C analogues. Tryptamine derivatives have an affinity for 5-HT1A, 5-HT2A and 5-HT2C receptors, and can inhibit reuptake and increase the release of serotonin.…”