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

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.