Design of Small Non-Peptidic Ligands That Alter Heteromerization between Cannabinoid CB<sub>1</sub> and Serotonin 5HT<sub>2A</sub> Receptors
Activation of cannabinoid CB<sub>1</sub> receptors (CB<sub>1</sub>R) by agonists induces analgesia but also induces cognitive impairment through the heteromer formed between CB<sub>1</sub>R and the serotonin 5HT<sub>2A</sub> receptor (5HT<sub>2A</sub>R). This side effect poses a serious drawback in the therapeutic use of cannabis for pain alleviation. Peptides designed from the transmembrane helices of CB<sub>1</sub>R, which are predicted to bind 5HT<sub>2A</sub>R and alter the stability of the CB<sub>1</sub>R-5HT<sub>2A</sub>R heteromer, have been shown to avert CB<sub>1</sub>R agonist-induced cognitive impairment while preserving analgesia. Using these peptides as templates, we have now designed nonpeptidic small molecules that prevent CB<sub>1</sub>R-5HT<sub>2A</sub>R 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 CB<sub>1</sub>R-5HT<sub>2A</sub>R heteromer, opening new perspectives for <i>in vivo</i> studies.
Authors
- Sergi Ferré (ORCID: https://orcid.org/0000-0002-1747-1779)
- Vicent Casadó
- Leonardo Pardo (ORCID: https://orcid.org/0000-0003-1778-7420)
- Estefanía Moreno (ORCID: https://orcid.org/0000-0002-2491-5753)
- Minos–Timotheos Matsoukas (ORCID: https://orcid.org/0000-0002-4642-8163)
- Maria Gallo (ORCID: https://orcid.org/0000-0001-9099-7235)
- David Andreu (ORCID: https://orcid.org/0000-0002-6317-6666)
- Marc Ciruela-Jardí (ORCID: https://orcid.org/0009-0001-9920-8789)
Institutions
- Universitat Autònoma de Barcelona (ES)
- National Institutes of Health (US)
- National Institute on Drug Abuse (US)
- Universitat Pompeu Fabra (ES)
- Institut Barcelona d'Estudis Internacionals (ES)
- University of West Attica (GR)
- Institute for Biomedicine (IT)
- Institute for Research in Biomedicine (ES)
- Caris Life Sciences (United States) (US)
- Office of Extramural Research (US)
- Instituto de Medicina Genómica (ES)
- Max Planck Institute for Molecular Biomedicine (DE)
- Universitat de Barcelona (ES)
Publication Details
- Journal
- Journal of Medicinal Chemistry
- Published
- 2024-12-27
- DOI
- https://doi.org/10.1021/acs.jmedchem.4c01796
- Citations
- 7
- Primary Topic
- Cannabis and Cannabinoid Research
- Type
- article
- Field-Weighted Citation Impact
- 3.13
Funders
- Generalitat de Catalunya
- Ministerio de Economía y Competitividad
- Ministerio de Ciencia e Innovación
- Barcelona Supercomputing Center
- European Regional Development Fund
- National Institute on Drug Abuse