Conformational Restriction of Designer Drugs Reveals Subtype-Selective and Biased CB<sub>2</sub> Agonists with Neuroprotective Effects
This study presents the design, synthesis, and characterization of a novel series of structurally simple, selective, and functionally biased CB<sub>2</sub> receptor (CB<sub>2</sub>R) agonists with potent anti-inflammatory and neuroprotective properties. These compounds were developed using a conformational restriction strategy to abolish CB<sub>1</sub>R binding, thereby enhancing CB<sub>2</sub>R selectivity. Pharmacological profiling identified ligands with distinct bias toward β-arrestin, MAPK, and G-protein signaling pathways. The series exhibits favorable drug-like properties, including high BBB permeability, low P-glycoprotein interaction, and microsomal stability. Representative compounds demonstrated neuroprotective activity in mouse primary neuronal assays and significantly reduced ROS and caspase levels <i>in vitro</i>, indicating mitigation of oxidative stress and apoptosis. In a neuron-like SH-SY5Y model expressing pathogenic mutations, they preserved neurite complexity in a CB<sub>2</sub>R-dependent manner. Collectively, these findings highlight the advantages of conformational restriction in transforming abused promiscuous, neurotoxic ligands into highly selective and efficacious agents for the treatment of neurodegenerative disorders, without CB<sub>1</sub>R-mediated psychoactive effects.
Authors
- Xerardo Garcı́a-Mera (ORCID: https://orcid.org/0000-0001-5218-6351)
- Rubén Prieto‐Díaz (ORCID: https://orcid.org/0000-0003-2539-3106)
- Chiara Riganti (ORCID: https://orcid.org/0000-0001-9787-4836)
- Giuseppe Felice Mangiatordi (ORCID: https://orcid.org/0000-0003-4042-2841)
- Gemma Navarro (ORCID: https://orcid.org/0000-0003-4654-0873)
- Claudia Gioé-Gallo (ORCID: https://orcid.org/0000-0002-2075-6863)
- Maria Grazia Perrone (ORCID: https://orcid.org/0000-0003-4195-5228)
- Angela Stefanachi (ORCID: https://orcid.org/0000-0002-9430-7972)
- Asier Selas (ORCID: https://orcid.org/0000-0001-7327-668X)
- Aitor García-Rey (ORCID: https://orcid.org/0000-0003-1633-872X)
- Joan Biel Rebassa (ORCID: https://orcid.org/0000-0002-3111-1550)
- Antonio Andújar-Arias (ORCID: https://orcid.org/0000-0001-9922-3543)
- Jose Manuel Brea (ORCID: https://orcid.org/0000-0002-5523-1979)
- Jhonny Azuaje (ORCID: https://orcid.org/0000-0001-9726-0455)
- Giovanni Graziano (ORCID: https://orcid.org/0000-0002-5575-3240)
- M. Rita Paleo (ORCID: https://orcid.org/0000-0002-0095-3931)
- Marı́a Isabel Loza (ORCID: https://orcid.org/0000-0003-4730-0863)
- Domenico Alberga (ORCID: https://orcid.org/0000-0002-9475-9602)
- Antón L. Martínez (ORCID: https://orcid.org/0000-0002-1595-3459)
- Eddy Sotelo (ORCID: https://orcid.org/0000-0001-5571-2812)
- David Reza (ORCID: https://orcid.org/0000-0002-6075-0079)
- Cristina Val (ORCID: https://orcid.org/0009-0001-8761-8545)
- Marialessandra Contino (ORCID: https://orcid.org/0000-0002-0713-3151)
- Sandra Ortigueira (ORCID: https://orcid.org/0000-0001-9544-2394)
- Fabio Francavilla (ORCID: https://orcid.org/0009-0004-3921-7597)
Institutions
- Universidade de Santiago de Compostela (ES)
- Institute of Food Science and Technology (CN)
- Center for Research in Molecular Medicine and Chronic Diseases (ES)
- Institute of Crystallography (IT)
- University of Turin (IT)
- University of Bari Aldo Moro (IT)
- Universitat de Barcelona (ES)
Publication Details
- Journal
- Journal of Medicinal Chemistry
- Published
- 2025-08-12
- DOI
- https://doi.org/10.1021/acs.jmedchem.5c00604
- Citations
- 2
- Primary Topic
- Cannabis and Cannabinoid Research
- Type
- article
- Field-Weighted Citation Impact
- 2.79
Funders
- European Cooperation in Science and Technology
- Consellería de Cultura, Educación e Ordenación Universitaria, Xunta de Galicia
- Xunta de Galicia
- Centro Singular de Investigación de Galicia
- European Regional Development Fund
- Agencia Estatal de Investigación