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 DOI: 10.1038/s41380-025-03325-1 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Experimental study Peer reviewed |
|---|---|
| Population | Mice |
| Intervention | 5-dimethoxyamphetamine |
| Topics | Serotonin |
| Keywords | In vivo Potency In vitro Pharmacokinetics Intrinsic activity Structure–activity relationship Pharmacology Drug Biochemistry Cricetulus 5-ht1a receptor Biological activity Stereochemistry |
| Citations | 1 |
| Key findings | Extending the 4-position alkyl chain of 2,5-dimethoxyamphetamines beyond a propyl group reduces in vivo potency and efficacy, partly due to pharmacokinetic parameters. |
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.
Comparable studies
Other preclinical and animal studies on serotonin, most cited first.
| Study | Year | Design | Participants |
|---|---|---|---|
| Psilocybin induces rapid and persistent growth of dendritic spines in frontal cortex in vivo Mice | 2021 | Observational cohort | |
| Neurotoxicity of the psychedelic amphetamine, methylenedioxymethamphetamine. Rats (implied by typical neurochemical study context) | 1987 | Experimental study | |
| Psychedelics promote neuroplasticity through the activation of intracellular 5-HT2A receptors In vitro and in vivo (rodent) models | 2023 | Experimental study | |
| 3,4-Methylenedioxymethamphetamine and 3,4-methylenedioxyamphetamine destroy serotonin terminals in rat brain: quantification of neurodegeneration by measurement of [3H]paroxetine-labeled serotonin uptake sites. Rat brain | 1987 | Animal experiment | |
| Comparison of the monoamine transporters from human and mouse in their sensitivities to psychostimulant drugs Human and mouse dopamine, norepinephrine, and serotonin transporters expressed in cells | 2006 | In vitro laboratory study |
Citations in the library
Cited by 2
- 5‐HT 2A receptor agonism by tert ‐leucinamide and valinamide synthetic cannabinoids: In vitro and in vivo evidence British Journal of Pharmacology May 5, 2026
- Exploring a Druggable Hydrophobic Tunnel in the 5-HT2A Receptor with Potent Phenethylamines Journal of Medicinal Chemistry September 25, 2026
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and 60 more in the library