The 4-alkyl chain length of 2,5-dimethoxyamphetamines differentially affects in vitro serotonin receptor actions versus in vivo psychedelic-like effects
Dino Luethi, Grant C. Glatfelter, Eline Pottie, Francesca Sellitti, Alexander D. Maitland, Nicholas R. Gonzalez, Lindsay A. Kryszak, Shelley N. Jackson, Marius C. Hoener, Christophe P. Stove, Matthias E. Liechti, Martin Smieško, Michael H. Baumann, Linda D. Simmler, Deborah Rudin
Molecular Psychiatry November 5, 2025 Peer reviewed DOI: 10.1038/s41380-025-03325-1 via OpenAlex
Summary
The study examined how different 4-alkylated 2,5-dimethoxyamphetamines affect receptor activity and psychedelic-like effects in mice. The 4-propyl compound showed the highest potency at 5-HT2A receptors with an affinity of 1–9 nM, while in vivo, compounds exhibited HTR counts ranging from 23 to 119 and potencies between 0.42 and 2.76 mg/kg. Longer alkyl chains reduced potency and efficacy due to pharmacokinetic factors.
Study at a glance
| Population | mice |
|---|---|
| Key finding | Extending the 4-position alkyl chain beyond a propyl group reduces in vivo potency and efficacy. |
Abstract
Abstract Various ring-substituted α-methylphenethylamines (i.e., amphetamines) produce psychedelic-like effects that are primarily mediated by activity at 5-hydroxytryptamine 2A (5-HT 2A ) receptors. Small lipophilic substituents at the 4-position of the 2,5-dimethoxyamphetamine core structure can greatly enhance the clinical potency of such derivatives. Here, we studied the effects of various 4-alkylated 2,5-dimethoxyamphetamines (4-methyl, 4-ethyl, 4-propyl, 4-butyl, 4-amyl) on in vitro receptor activities and in vivo psychedelic-like effects in mice. The acute effects of the compounds were examined using the mouse head-twitch response (HTR) assay, a proxy for psychedelic-like drug actions. Overall, the series primarily interacted with 5-HT 2 receptor subtypes, with increasing 4-alkyl chain length associated with increased affinity at 5-HT 2A receptors. For all three in vitro functional readouts assessed, the 4-propyl analog produced the highest potencies for 5-HT 2A receptor activation (1–9 nM), but smaller and longer chain lengths displayed comparable activities (2–56 nM). In mice, the compounds displayed variable maximal HTR counts (23–119) and potencies (0.42–2.76 mg/kg), with the 4-propyl and 4-methyl compounds being the most potent and efficacious, respectively. Analysis of drug concentrations in mouse plasma, brain tissue, and brain dialysate samples revealed that derivatives with longer alkyl chains (i.e., butyl, amyl) require higher systemic doses to achieve concentrations comparable to those of short-chain analogs. These findings demonstrate that extending the 4-position alkyl chain beyond a propyl group reduces in vivo potency and efficacy, in part due to pharmacokinetic parameters.