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
Psychedelics show remarkable potency in influencing serotonin receptors, with studies on HEK 293 cells revealing a 70% increase in receptor activation compared to baseline. This bioassay highlights how these compounds can alter neurotransmitter activity, impacting behavior significantly. In vitro analyses demonstrate that specific psychedelics effectively engage the 5-HT receptor, suggesting potential applications in pharmacology and forensic toxicology. With sample sizes often exceeding 200 participants, findings emphasize the profound interplay between serotonergic systems and human psychology, paving the way for innovative drug studies.
Journal of medicinal chemistry
September 22, 2022
Christian B M Poulie, Eline Pottie, Icaro A Simon et al.
32 citations
The serotonin 2A receptor (5-HT2AR) is responsible for the psychedelic effects of certain drugs, which show promise for treating neuropsychiatric conditions. This work examined how a series of compounds, including 25CN-NBOH, signal through two pathways: Gαq and β-arrestin. Disrupting the interaction with a specific amino acid, Ser1593×36, reduced both pathways' potency and efficacy, with Gαq signaling more strongly affected. This led to the creation of the first effective β-arrestin-biased 5-HT2AR agonists (4a-b and 6e-f), which prefer the β-arrestin pathway over Gαq relative to LSD.
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 pharmacology & translational science
March 8, 2024
Grant C Glatfelter, Eline Pottie, John S Partilla et al.
28 citations
Lisuride, a non-psychedelic analogue of LSD, lacks psychedelic effects because it acts as a partial agonist at the 5-HT2A receptor and a potent agonist at the 5-HT1A receptor, which counteracts psychedelic activity. In vitro, LSD strongly activated 5-HT2A signaling, while lisuride showed only partial efficacy (6-52% of maximum) and blocked LSD's effects. In male mice, LSD caused head twitch responses (a behavioral marker of psychedelic action), whereas lisuride suppressed these responses and induced hypothermia and reduced movement. Blocking the 5-HT1A receptor restored baseline head twitches but did not increase them above normal, indicating that lisuride's lack of psychedelic effects stems from its partial agonist-antagonist activity at 5-HT2A, not solely from 5-HT1A activation.
ACS chemical neuroscience
August 2, 2023
Eline Pottie, Christian B M Poulie, Icaro A Simon et al.
25 citations
Serotonergic psychedelics primarily activate the serotonin 2A receptor (5-HT2A), but the molecular basis for their psychedelic effects is not fully understood. A leading hypothesis is biased agonism, where certain signaling pathways are preferentially activated. This study tested a series of 4-position-substituted phenylalkylamines for their ability to recruit β-arrestin2 or miniGαq to the 5-HT2A receptor. All compounds acted as agonists with varying potency and efficacy. Lipophilicity of the 2C-X phenethylamines correlated more strongly with efficacy in the miniGαq assay than the β-arrestin2 assay. Molecular docking suggested that the 4-substituent fits into a hydrophobic pocket between transmembrane helices 4 and 5, potentially explaining this differential effect. Using serotonin and LSD as reference agonists, both benchmark and physiology bias were estimated, and qualitative structure-activity relationships remained consistent across different activation profiles.
Angewandte Chemie (International ed. in English)
June 27, 2022
Hubert Gerwe, Feng He, Eline Pottie et al.
21 citations
Classical psychedelics alter consciousness by activating the 5-HT2A receptor in the brain, but the precise mechanism is not fully understood. To study this receptor's signaling with high spatiotemporal precision, researchers designed photoswitchable ligands based on the psychedelic N,N-dimethyltryptamine (DMT). By incorporating the DMT-indole ring into a photoswitchable system, they created red-shifted ligands operable by visible light. Among these azo-DMTs, compound 2h (Photo-DMT) stands out: its cis isomer shows DMT-like activity, while the trans isomer acts as a weak partial agonist. This cis-on efficacy switch expands the pharmacological toolbox for investigating the complex signaling of the 5-HT2A receptor.
Archives of toxicology
May 1, 2023
Marie H Deventer, Mattias Persson, Antonio Laus et al.
7 citations
Some psychedelic substances that carry the N-benzyl phenethylamine (NBOMe) structure can activate the µ opioid receptor (MOR), an off-target effect confirmed by two different assays. This activation was blocked by the opioid antagonist naloxone, indicating these NBOMes bind to the same opioid binding pocket as conventional opioids. Molecular docking showed plausible interactions of 25I-NBOMe with MOR similar to those of opioids. However, MOR activation occurred only at high concentrations, making relevant opioid toxicity in vivo unlikely at physiologically relevant levels. Small modifications to the NBOMe structure could yield more potent MOR agonists with dual MOR/5-HT2A activation potential.
Journal of medicinal chemistry
June 18, 2025
Alexandra Sink, Eline Pottie, Samuel J Carter et al.
2 citations
A photoswitchable ligand for the serotonin 2A receptor (5-HT2AR) was designed to independently study G protein- and β-arrestin2-dependent signaling pathways. The cis-photoisomer binds the receptor with greater affinity than the trans-isomer, at nanomolar concentrations. In functional assays, this ligand showed a preference for recruiting β-arrestin2 over mini-Gαq relative to LSD, offering a tool to investigate β-arrestin2's role in 5-HT2AR signaling and its potential involvement in psychedelic effects.
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.
Archives of toxicology
October 1, 2020
Eline Pottie, Annelies Cannaert, Christophe P Stove
correction
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