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.
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.