Pharmacological fingerprint of antipsychotic drugs at the serotonin 5-HT2A receptor

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• dc.contributor.author Gaitonde, Supriya A.
• dc.contributor.author Avet, Charlotte
• dc.contributor.author de la Fuente Revenga, Mario
• dc.contributor.author Blondel-Tepaz, Elodie
• dc.contributor.author Shahraki, Aida
• dc.contributor.author Morales Pastor, Adrián
• dc.contributor.author Talagayev, Valerij
• dc.contributor.author Robledo, Patricia, 1958-
• dc.contributor.author Kolb, Peter
• dc.contributor.author Selent, Jana
• dc.contributor.author González-Maeso, Javier
• dc.contributor.author Bouvier, Michel
• dc.date.accessioned 2025-07-07T06:33:13Z
• dc.date.available 2025-07-07T06:33:13Z
• dc.date.issued 2024
• dc.description.abstract The intricate involvement of the serotonin 5-HT2A receptor (5-HT2AR) both in schizophrenia and in the activity of antipsychotic drugs is widely acknowledged. The currently marketed antipsychotic drugs, although effective in managing the symptoms of schizophrenia to a certain extent, are not without their repertoire of serious side effects. There is a need for better therapeutics to treat schizophrenia for which understanding the mechanism of action of the current antipsychotic drugs is imperative. With bioluminescence resonance energy transfer (BRET) assays, we trace the signaling signature of six antipsychotic drugs belonging to three generations at the 5-HT2AR for the entire spectrum of signaling pathways activated by serotonin (5-HT). The antipsychotic drugs display previously unidentified pathway preference at the level of the individual Gα subunits and β-arrestins. In particular, risperidone, clozapine, olanzapine and haloperidol showed G protein-selective inverse agonist activity. In addition, G protein-selective partial agonism was found for aripiprazole and cariprazine. Pathway-specific apparent dissociation constants determined from functional analyses revealed distinct coupling-modulating capacities of the tested antipsychotics at the different 5-HT-activated pathways. Computational analyses of the pharmacological and structural fingerprints support a mechanistically based clustering that recapitulate the clinical classification (typical/first generation, atypical/second generation, third generation) of the antipsychotic drugs. The study provides a new framework to functionally classify antipsychotics that should represent a useful tool for the identification of better and safer neuropsychiatric drugs and allows formulating hypotheses on the links between specific signaling cascades and in the clinical outcomes of the existing drugs.
• dc.format.mimetype application/pdf
• dc.identifier.citation Gaitonde SA, Avet C, de la Fuente Revenga M, Blondel-Tepaz E, Shahraki A, Pastor AM, et al. Pharmacological fingerprint of antipsychotic drugs at the serotonin 5-HT2A receptor. Mol Psychiatry. 2024 Sep;29(9):2753-64. DOI: 10.1038/s41380-024-02531-7
• dc.identifier.doi http://dx.doi.org/10.1038/s41380-024-02531-7
• dc.identifier.issn 1359-4184
• dc.identifier.uri http://hdl.handle.net/10230/70846
• dc.language.iso eng
• dc.publisher Nature Research
• dc.relation.ispartof Mol Psychiatry. 2024 Sep;29(9):2753-64
• dc.rights © The Author(s) 2024. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.
• dc.rights.accessRights info:eu-repo/semantics/openAccess
• dc.rights.uri http://creativecommons.org/licenses/by/4.0/
• dc.title Pharmacological fingerprint of antipsychotic drugs at the serotonin 5-HT2A receptor
• dc.type info:eu-repo/semantics/article
• dc.type.version info:eu-repo/semantics/publishedVersion