In vitro assays for the functional characterization of (psychedelic) substances at the serotonin receptor 5‐HT2AR
Eline Pottie, Christophe P Stove
Journal of Neurochemistry January 3, 2022 DOI: 10.1111/jnc.15570 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Review Peer reviewed |
|---|---|
| Topics | Serotonin |
| Key findings | The review catalogs in vitro assays used to characterize psychedelic 5-HT2A receptor agonists, spanning canonical G protein signaling (G protein recruitment/activation, inositol phosphate accumulation, calcium mobilization), non-canonical G protein signaling such as arachidonic acid release, beta-arrestin recruitment or signaling, and receptor conformational changes. It argues that the structural variety of these substances leaves structure-activity relationships insufficiently described, and that assay mechanism and execution variables can heavily affect functional outcomes, complicating comparisons across studies. |
Abstract
Serotonergic psychedelics are substances that induce alterations in mood, perception, and thought, and have the activation of serotonin (5‐HT) 2A receptors (5‐HT2ARs) as a main pharmacological mechanism. Besides their appearance on the (illicit) drug market, e.g. as new psychoactive substances, their potential therapeutic application is increasingly explored. This group of substances demonstrates a broad structural variety, leading to insufficiently described structure‐activity relationships, hence illustrating the need for better functional characterization. This review therefore elaborates on the in vitro molecular techniques that have been used the most abundantly for the characterization of (psychedelic) 5‐HT2AR agonists. More specifically, this review covers assays to monitor the canonical G protein signaling pathway (e.g. measuring G protein recruitment/activation, inositol phosphate accumulation, or Ca2+ mobilization), assays to monitor non‐canonical G protein signaling (such as arachidonic acid release), assays to monitor β‐arrestin recruitment or signaling, and assays to monitor receptor conformational changes. In particular, focus lies on the mechanism behind the techniques, and the specific advantages and challenges that are associated with these. Additionally, several variables are discussed that one should consider when attempting to compare functional outcomes from different studies, both linked to the specific assay mechanism and linked to its specific execution, as these may heavily impact the assay outcome.
Comparable studies
Other narrative reviews on serotonin, most cited first.
Citations in the library
Cited by 23
- Structure–Activity Relationships for Psilocybin, Baeocystin, Aeruginascin, and Related Analogues to Produce Pharmacological Effects in Mice ACS Pharmacology & Translational Science November 2, 2022
- Serotonin 2A Receptor (5-HT2AR) Agonists: Psychedelics and Non-Hallucinogenic Analogues as Emerging Antidepressants Chemical Reviews November 30, 2023
- Discovery of β-Arrestin-Biased 25CN-NBOH-Derived 5-HT2A Receptor Agonists. Journal of Medicinal Chemistry September 22, 2022
- Ethopharmacological evaluation of antidepressant-like effect of serotonergic psychedelics in C57BL/6J male mice. Naunyn-Schmiedeberg's Archives of Pharmacology May 1, 2024
- Comparative Pharmacological Effects of Lisuride and Lysergic Acid Diethylamide Revisited. ACS Pharmacology & Translational Science March 8, 2024
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