Monoamine Receptor and Transporter Interaction Profiles of 4‐Alkyl‐Substituted 2,5‐Dimethoxyamphetamines

Summary

The pharmacological properties of 4-alkylated 2,5-dimethoxyamphetamines were examined in vitro, focusing on how the length of the 4-alkyl chain affects interactions with monoaminergic targets. The 4-alkylated derivatives (DOM, DOET, DOBU, DOAM) showed potent nanomolar affinity at serotonin 5-HT2A and 5-HT2C receptors, unlike the parent compound 2,5-DMA. Increasing alkyl chain length enhanced selectivity for 5-HT2A over 5-HT1A and 5-HT2C receptors. DOM and DOET activated the 5-HT2B receptor as partial agonists (EC50: 68–128 nM, Emax: 73–85%), while DOBU and DOAM did not (EC50 > 10,000 nM). The derivatives showed weak or no interaction with other monoaminergic targets. The findings suggest that 5-HT2A and 5-HT2C receptor affinity alone does not sufficiently predict clinical or psychedelic potency.

Study at a glance

Abstract

Background Various ring‐substituted phenethylamines and amphetamines are used recreationally due to their mind‐altering effects. Furthermore, such psychedelic substances have recently gained increased interest as prospective therapeutics. Here, we studied the pharmacological properties of 4‐alkylated 2,5‐dimethoxyamphetamines in vitro. Specifically, we assessed the effect of the 4‐alkyl chain length on interactions with monoaminergic targets. We aimed to test the hypothesis that the derivatives with the highest clinical potency display the most potent serotonin (5‐HT) type 2A receptor interactions, which is the key driver of psychedelic effects. Methods We determined binding affinities of 2,5‐dimethoxyamphetamine (2,5‐DMA), 4‐methyl‐2,5‐dimethoxyamphetamine (DOM), 4‐ethyl‐2,5‐dimethoxyamphetamine (DOET), 4‐butyl‐2,5‐dimethoxyamphetamine (DOBU), and 4‐amyl‐2,5‐dimethoxyamphetamine (DOAM) at serotonergic, adrenergic, and dopaminergic receptors and transporters, as well as at the trace amine‐associated receptor 1 (TAAR1). For this, we assessed radioligand displacement using cell membrane preparations expressing the respective targets. Furthermore, we determined the functional activity of the derivatives at the 5‐HT 2A and 5‐HT 2B receptors by measuring calcium mobilization and at the TAAR1 by measuring cAMP accumulation. In addition, we assessed whether any of the derivatives inhibit transporter‐mediated uptake of radiolabeled monoamines. Results Unlike 2,5‐DMA, its 4‐alkylated derivatives displayed potent (i.e., nanomolar) affinity at 5‐HT 2A and 5‐HT 2C receptors. Increasing length of the 4‐alkyl chain increased the selectivity for 5‐HT 2A vs. 5‐HT 1A and 5‐HT 2C receptors. Whereas DOM and DOET activated the 5‐HT 2B receptor as partial agonists in the nanomolar range (EC 50 : 68–128 nM, E max : 73–85%), DOBU and DOAM did not activate the receptor at investigated concentrations (EC 50 > 10,000 nM). In contrast to the potent interactions with 5‐HT 2 receptors, the 4‐alkyl‐substituted 2,5‐dimethoxyamphetamines did not or only weakly (i.e., in the micromolar range) interact with other monoaminergic targets. Conclusion Among the tested substances, user reports suggest DOM and DOET to be the only derivatives with a distinct psychedelic effect profile. Our data therefore indicate that 5‐HT 2A and 5‐HT 2C receptor affinity alone is not a sufficient predictor for the clinical and psychedelic potency of 4‐substituted 2,5‐dimethoxyamphetamines. To assess the clinical potential of the tested substances, future studies should focus in more detail on pharmacokinetics and qualitative differences in 5‐HT 2 receptor activation.