Structure-Activity Assessment and In-Depth Analysis of Biased Agonism in a Set of Phenylalkylamine 5-HT2A Receptor Agonists.
Eline Pottie, Christian B M Poulie, Icaro A Simon, Kasper Harpsøe, Laura D'Andrea, Igor V Komarov, David E Gloriam, Anders A. Jensen, Jesper L. Kristensen, Christophe P Stove
ACS Chemical Neuroscience August 2, 2023 DOI: 10.1021/acschemneuro.3c00267 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | In vitro pharmacological study Qualitative Peer reviewed |
|---|---|
| Topics | Serotonin |
| Keywords | 5-ht2a Biased agonism In vitro pharmacology Minigαq Psychedelics Β-arrestin Psychopharmacology Molecular signaling Receptor biology Drug mechanisms |
| Citations | 25 |
| Key points | Lipophilicity of 2C-X phenethylamines correlates more strongly with efficacy in miniGαq recruitment than in β-arrestin2 recruitment to the 5-HT2A receptor, suggesting biased agonism. |
Abstract
Serotonergic psychedelics are described to have activation of the serotonin 2A receptor (5-HT2A) as their main pharmacological action. Despite their relevance, the molecular mechanisms underlying the psychedelic effects induced by certain 5-HT2A agonists remain elusive. One of the proposed hypotheses is the occurrence of biased agonism, defined as the preferential activation of certain signaling pathways over others. This study comparatively monitored the efficiency of a diverse panel of 4-position-substituted (and N-benzyl-derived) phenylalkylamines to induce recruitment of β-arrestin2 (βarr2) or miniGαq to the 5-HT2A, allowing us to assess structure-activity relationships and biased agonism. All test compounds exhibited agonist properties with a relatively large range of both EC50 and Emax values. Interestingly, the lipophilicity of the 2C-X phenethylamines was correlated with their efficacy in both assays but yielded a stronger correlation in the miniGαq- than in the βarr2-assay. Molecular docking suggested that accommodation of the 4-substituent of the 2C-X analogues in a hydrophobic pocket between transmembrane helices 4 and 5 of 5-HT2A may contribute to this differential effect. Aside from previously used standard conditions (lysergic acid diethylamide (LSD) as a reference agonist and a 2 h activation profile to assess a compound's activity), serotonin was included as a second reference agonist, and the compounds' activities were also assessed using the first 30 min of the activation profile. Under all assessed circumstances, the qualitative structure-activity relationships remained unchanged. Furthermore, the use of two reference agonists allowed for the estimation of both "benchmark bias" (relative to LSD) and "physiology bias" (relative to serotonin).
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 22
- Discovery of β-Arrestin-Biased 25CN-NBOH-Derived 5-HT2A Receptor Agonists. Journal of Medicinal Chemistry September 22, 2022
- Comparative Pharmacological Effects of Lisuride and Lysergic Acid Diethylamide Revisited. ACS Pharmacology & Translational Science March 8, 2024
- A Comprehensive Review of the Current Status of the Cellular Neurobiology of Psychedelics Biology October 28, 2023
- The mechanistic divide in psychedelic neuroscience: An unbridgeable gap? Neurotherapeutics January 25, 2024
- Psilocybin as Transformative Fast‐Acting Antidepressant: Pharmacological Properties and Molecular Mechanisms Fundamental and Clinical Pharmacology July 16, 2025
and 17 more in the library
Cites 34
- Evidence for 5-HT2 involvement in the mechanism of action of hallucinogenic agents. Life Sciences December 17, 1984
- Psychedelics promote neuroplasticity through the activation of intracellular 5-HT2A receptors Science February 16, 2023
- Crystal structure of an LSD-bound human serotonin receptor Cell January 26, 2017
- Structure-based discovery of nonhallucinogenic psychedelic analogs Science January 27, 2022
- Hallucinogens and Serotonin 5-HT2A Receptor-Mediated Signaling Pathways Current Topics in Behavioral Neurosciences 2017
and 29 more in the library