ACS chemical neuroscience
March 19, 2014
Martin Hansen, Karina Phonekeo, James S Paine et al.
125 citations
Adding a benzyl group to the nitrogen atom of phenethylamine psychedelics like 2C-B greatly increases their binding and activity at serotonin 5-HT2A receptors. A library of 48 compounds with varied phenethylamine and N-benzyl structures was tested. Most had high 5-HT2A affinity; compound 8b showed the highest affinity at 0.29 nM, while 1b was the most functionally potent at 0.074 nM. Selectivity over the related 5-HT2C receptor ranged from 1- to 40-fold in binding, though 6b achieved 100-fold selectivity. Functional selectivity was higher, with 1b exceeding 400-fold selectivity for 5-HT2A.
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.
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.
Pharmacological reviews
October 1, 2022
Anna U Odland, Jesper L Kristensen, Jesper T Andreasen
23 citations
Psychedelic-assisted psychotherapy shows promise for treating mental health disorders, and research on 5-HT2AR agonist psychedelics has grown rapidly. In humans, these compounds alter consciousness and affect emotional, social, and self-referential information processing. The translational value of animal behavior studies is debated. In rodents, acute psychedelic treatment produces head twitches, disrupts sensorimotor gating, stimulates motor activity, inhibits exploration, and shows anxiolytic-like effects while inhibiting repetitive behavior. Effects on depression-like behaviors, cognitive function, and social interaction are discrepant. Lasting effects are sensitive to experimental protocols. Improving animal studies by assessing lasting effects, publishing negative findings, and relating behaviors to neuroplastic changes will enhance translational value.
ACS chemical neuroscience
May 6, 2020
Emil Marcher-Rørsted, Adam L Halberstadt, Adam K Klein et al.
20 citations
The 2,5-dimethoxy motif found in many phenethylamine psychedelics has been considered essential for activating the serotonin 2A receptor (5-HT2AR). This study synthesized derivatives of 2C-B and DOB lacking either the 2- or 5-methoxy group and tested them in binding and functional assays at 5-HT2AR and 5-HT2CR, as well as in mice for head-twitch response, a behavioral proxy for psychedelic activity. Removing either methoxy group caused a modest drop in binding affinity and functional potency at both receptors, with larger effects from removing the 2-methoxy group. However, in mice, removal of either group drastically reduced head-twitch response. Thus, the 2,5-dimethoxy motif is important for in vivo potency, but this does not correlate with in vitro receptor affinity or potency.
Journal of natural products
August 27, 2021
Camilla B Chan, Christian B M Poulie, Simon S Wismann et al.
13 citations
The term 'false peyote' is commonly applied to Lophophora diffusa, but several other unrelated cacti also share this name due to their resemblance to true peyote (Lophophora williamsii) or similar habitats. Over 40 alkaloids have been isolated from the Lophophora genus, yet only mescaline's pharmacological effects are well-studied. The major alkaloid in L. diffusa is pellotine, a tetrahydroisoquinoline briefly marketed as a sleeping aid in the early 1900s based on reports of its hypnotic properties. Pharmacological experiments on these alkaloids occurred around 1900, with chemical synthesis achieved decades later and biosynthetic pathways reported in the late 1960s. This review outlines the relationship of false peyotes to L. williamsii regarding alkaloid content, synthesis, and pharmacology.
Synapse (New York, N.Y.)
March 1, 2025
Yang Wang, Jesper L Kristensen, Kristi A Kohlmeier
5 citations
The synthetic psychedelic 25CN-NBOH, which binds strongly to serotonin type 2A receptors, has a dual effect on neurons in the mouse medial prefrontal cortex. Acute application of a high concentration (10 µM) increased the frequency of spontaneous excitatory postsynaptic currents, an effect dependent on serotonin 2A receptor activation and not seen with chronic exposure or a lower concentration (200 nM). However, both concentrations suppressed the firing rate of pyramidal neurons after acute and one-hour exposure. This suppression was independent of serotonin 2A receptors but mediated by M-current channels, as blocking M-currents reversed it. The compound thus enhances excitatory transmission while reducing overall excitability, revealing complex cellular actions that may underlie its therapeutic effects.