ACS Pharmacology & Translational Science
November 2, 2022
Eline Pottie, Marilyn Naeem, Vamshikrishna Reddy Sammeta et al.
91 citations
Psilocybin is a prodrug for psilocin, which produces psychedelic effects by activating serotonin 5-HT2A receptors. This study examined three naturally occurring compounds from psilocybin-containing mushrooms—psilocybin, baeocystin, and aeruginascin—along with their synthetic 4-acetoxy and 4-hydroxy analogues. In cell-based assays, secondary and tertiary tryptamines with 4-acetoxy or 4-hydroxy substitutions showed nanomolar affinity for several human serotonin receptor subtypes, including 5-HT2A and 5-HT1A. In mice, only the tertiary amines psilocin, psilocybin, and psilacetin induced head twitch responses (ED50 0.11–0.29 mg/kg), indicating psychedelic-like activity, which was blocked by a 5-HT2A antagonist.
Archives of Toxicology
July 5, 2020
Eline Pottie, Annelies Cannaert, Christophe P. Stove
36 citations
Serotonergic psychedelics, which act mainly through the serotonin 2A receptor, make up many new psychoactive substances. A stable cell-based bioassay using HEK 293 T cells was developed to monitor β-arrestin 2 recruitment to the 5-HT2AR. After verifying its performance against a transient transfection system, the assay was used to test 30 phenylalkylamine psychedelics: 12 phenethylamine derivatives (2C-X), 7 phenylisopropylamines (DOx), and 11 N-benzylderivatives (25X-NB). The resulting potency and efficacy values confirm findings from other in vitro assays and show a significant correlation with estimated common doses. This approach offers pharmacological insights and may help prioritize legal actions regarding the most potent compounds.
Analytical Chemistry
November 14, 2019
Eline Pottie, Annelies Cannaert, Katleen van Uytfanghe et al.
29 citations
Classic hallucinogens, which activate the serotonin 2A receptor (5-HT2AR), represent the third largest category of new psychoactive substances. A new bioassay was developed that measures receptor activation by monitoring β-arrestin2 recruitment using a split-luciferase system. The assay determined potency and efficacy for various hallucinogens, including LSD, 5-MeO-DALT, mescaline, and several 2C compounds and their NBOMe derivatives, with EC50 values ranging from subnanomolar (NBOMes) to micromolar (mescaline) levels. When applied to plasma screening, blank samples showed pronounced receptor activation due to endogenous serotonin, confirmed by its elimination with a 5-HT2AR antagonist or MAO-A treatment, and by LC-HRMS analysis. The bioassay's main application is characterizing poorly understood serotonergic hallucinogens, as MAO-A metabolism of some compounds could bias detection in biofluids.
ACS Omega
May 13, 2026
Darío Martínez-afani, Breno A. Soares, Jaime Mella-Raipán et al.
1 citation
A set of 22 tryptamine and 22 5-methoxytryptamine derivatives with various N-benzyl substituents were synthesized and tested for affinity and potency at serotonin 5-HT2A, 5-HT2B, and 5-HT2C receptors. The data enabled QSAR analysis, which showed that meta-substitution on the benzyl ring improves activity, while para-substitution reduces it. These effects are attributed to favorable van der Waals interactions at the meta position and steric hindrance at the para position. The findings suggest that N-benzyltryptamines, previously overlooked as psychedelic ligands, could be leads for treating cognitive disorders, substance abuse, or depression.
Molecular Psychiatry
November 5, 2025
Dino Luethi, Grant C. Glatfelter, Eline Pottie et al.
1 citation
Psychedelic-like effects of ring-substituted amphetamines are primarily mediated by 5-HT 2A receptors. Small lipophilic substituents at the 4-position of 2,5-dimethoxyamphetamine enhance clinical potency. This study examined 4-alkylated 2,5-dimethoxyamphetamines (methyl, ethyl, propyl, butyl, amyl) for in vitro receptor activity and in vivo effects in mice using the head-twitch response (HTR) assay. Increasing 4-alkyl chain length raised affinity at 5-HT 2A receptors. The 4-propyl analog showed the highest potencies for 5-HT 2A receptor activation (1–9 nM) in vitro; other chain lengths ranged from 2–56 nM. In mice, maximal HTR counts varied from 23 to 119, with potencies from 0.42 to 2.76 mg/kg.
Molecular Psychiatry
October 21, 2025
Pol Puigseslloses, Núria Nadal‐gratacós, Berta Fumàs et al.
1 citation
A novel class of halogenated DMT derivatives—5-F-DMT, 5-Cl-DMT, and 5-Br-DMT—was characterized for pharmacological activity and therapeutic potential. Halogen substitution at the 5-position modulates receptor affinity across serotonin receptors and the serotonin transporter. 5-Br-DMT activated the 5-HT2A receptor but did not induce the head twitch response in mice, suggesting non-hallucinogenic activity. It upregulated immediate early genes linked to neuroplasticity in the mouse prefrontal cortex and hippocampus and promoted dendritic growth in cortical neurons. A single 10 mg/kg dose of 5-Br-DMT in a mouse model of stress-induced depression significantly reduced depressive-like behavior, indicating rapid antidepressant effects. The findings highlight 5-Br-DMT as a non-hallucinogenic psychoplastogen with antidepressant properties.
Molecular Psychiatry
November 14, 2025
Núria Nadal‐gratacós, Pol Puigseslloses, Laura Hernández‐guzmán et al.
Three novel phenethylamine derivatives—25C-NBF, 25B-NBF, and 25I-NBF—show high affinity and selectivity for the 5-HT2A receptor, with signaling bias toward Gq over β-arrestin pathways similar to serotonin. In mice, they cause moderate head-twitch responses without affecting movement or sensorimotor gating. No rewarding or reinforcing effects were observed, and accumbal dopamine levels in rats remained unchanged. 25C-NBF promotes dendritogenesis, spinogenesis, and increased Bdnf mRNA in vitro and in vivo, reduces despair-like behavior after acute stress, and produces rapid antidepressant effects in a chronic corticosterone model of anhedonia. These findings suggest 25C-NBF may offer a fast-acting antidepressant with no abuse potential or sensorimotor deficits.