Design of small non-peptidic ligands that alter heteromerization between cannabinoid CB1 and serotonin 5HT2A receptors
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- dc.contributor.author Matsoukas, Minos-Timotheos
- dc.contributor.author Ciruela Jardí, Marc
- dc.contributor.author Gallo, María, 1989-
- dc.contributor.author Ferré, Sergi
- dc.contributor.author Andreu Martínez, David
- dc.contributor.author Casadó, Vicent
- dc.contributor.author Pardo, Leonardo
- dc.contributor.author Moreno, Estefanía
- dc.date.accessioned 2025-02-21T07:13:52Z
- dc.date.available 2025-02-21T07:13:52Z
- dc.date.issued 2025
- dc.description.abstract Activation of cannabinoid CB1 receptors (CB1R) by agonists induces analgesia but also induces cognitive impairment through the heteromer formed between CB1R and the serotonin 5HT2A receptor (5HT2AR). This side effect poses a serious drawback in the therapeutic use of cannabis for pain alleviation. Peptides designed from the transmembrane helices of CB1R, which are predicted to bind 5HT2AR and alter the stability of the CB1R-5HT2AR heteromer, have been shown to avert CB1R agonist-induced cognitive impairment while preserving analgesia. Using these peptides as templates, we have now designed nonpeptidic small molecules that prevent CB1R-5HT2AR heteromerization in bimolecular fluorescence complementation assays and the heteromerization-dependent allosteric modulations in cell signaling experiments. These results provide proof-of-principle for the design of optimized ligand-based disruptors of the CB1R-5HT2AR heteromer, opening new perspectives for in vivo studies.
- dc.description.sponsorship We acknowledge the financial support from the Spanish Ministry of Economy and Innovation with FEDER funds (projects PID2020-113938RB-I00, PID2022-140912OB-I00, and PID2023-146914OB-I00) and Generalitat de Catalunya (2021-SGR-00230 and 2021-SGR-00304). S.F. is funded with the intramural funds of the National Institute on Drug Abuse (ZIA DA000493). Work at MELIS-UPF is supported by the MCIN “María de Maeztu” program for units of excellence in R&D (CEX2018-000792-M). The authors thankfully acknowledge the computer resources at MareNostrum and the technical support provided by the Barcelona Supercomputing Center (RES-BCV-2024-2-0002).
- dc.format.mimetype application/pdf
- dc.identifier.citation Matsoukas MT, Ciruela-Jardí M, Gallo M, Ferre S, Andreu D, Casadó V, et al. Design of small non-peptidic ligands that alter heteromerization between cannabinoid CB1 and serotonin 5HT2A receptors. J Med Chem. 2025 Jan 9;68(1):261-9. DOI: 10.1021/acs.jmedchem.4c01796
- dc.identifier.doi http://dx.doi.org/10.1021/acs.jmedchem.4c01796
- dc.identifier.issn 0022-2623
- dc.identifier.uri http://hdl.handle.net/10230/69668
- dc.language.iso eng
- dc.publisher American Chemical Society (ACS)
- dc.relation.ispartof J Med Chem. 2025 Jan 9;68(1):261-9
- dc.relation.projectID info:eu-repo/grantAgreement/ES/2PE/PID2020-113938RB-I00
- dc.relation.projectID info:eu-repo/grantAgreement/ES/3PE/PID2022-140912OB-I00
- dc.relation.projectID info:eu-repo/grantAgreement/ES/3PE/PID2023-146914OB-I00
- dc.relation.projectID info:eu-repo/grantAgreement/ES/2PE/CEX2018-000792-M
- dc.rights © 2024 The Authors. Published by American Chemical Society. This publication is licensed under CC-BY 4.0 (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.subject.keyword Agonists
- dc.subject.keyword Aromatic compounds
- dc.subject.keyword Ligands
- dc.subject.keyword Peptides and proteins
- dc.subject.keyword Receptors
- dc.title Design of small non-peptidic ligands that alter heteromerization between cannabinoid CB1 and serotonin 5HT2A receptors
- dc.type info:eu-repo/semantics/article
- dc.type.version info:eu-repo/semantics/publishedVersion