(695.11) Monoamine Receptor and Transporter Interaction Profiles of 4-Alkyl-Substituted 2,5-Dimethoxyamphetamines

Poster Board Number: B69

Dino Luethi (University of Basel, University Hospital Basel, Medical University of Vienna), Deborah Rudin (University of Basel, University Hospital Basel), Marius Hoener (F. Hoffmann-La Roche Ltd), Matthias Liechti (University of Basel, University Hospital Basel)

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-HT2A and 5-HT2B 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-HT2A and 5-HT2C receptors. Increasing length of the 4-alkyl chain increased the selectivity for 5-HT2A vs. 5-HT1A and 5-HT2C receptors. Whereas DOM and DOET activated the 5-HT2B receptor as partial agonists in the nanomolar range (EC50: 68–128 nM, Emax: 73–85%), DOBU and DOAM did not activate the receptor at investigated concentrations (EC50 gt; 10,000 nM). In contrast to the potent interactions with 5-HT2 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-HT2A and 5-HT2C 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-HT2 receptor activation.

Support or Funding Information

This work was supported by the Swiss National Science Foundation (grant No. P400PM_191032 to D.L.) and the Federal Office of Public Health (grant No. 16.921318 to M.E.L.).