RT Journal Article
T1 Conformational Restriction of Designer Drugs Reveals Subtype-Selective and Biased CB2 Agonists with Neuroprotective Effects
A1 Prieto Díaz, Rubén
A1 Gioé Gallo, Claudia
A1 Ortigueira Noya, Sandra
A1 Prieto Díaz, Rubén
A1 García Mera, Xerardo
A1 Azuaje, Jhonny
A1 Andújar Arias, Antonio
A1 García Rey, Aitor
A1 Graciano, Giovanni
A1 Val García, Cristina
A1 Martínez Rodríguez, Antón Leandro
A1 Reza, David
A1 Selas Lanseros, Asier
A1 Francavilla, Fabio
A1 Paleo Pillado, María Rita
A1 Loza García, María Isabel
A1 Brea Floriani, José Manuel
A1 Sotelo Pérez, Eddy
K1 Agonists
K1 Amides
K1 Ligands
K1 Membranes
K1 Receptors
AB This study presents the design, synthesis, and characterization of a novel series of structurally simple, selective, and functionally biased CB2 receptor (CB2R) agonists with potent anti-inflammatory and neuroprotective properties. These compounds were developed using a conformational restriction strategy to abolish CB1R binding, thereby enhancing CB2R 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 in vitro, indicating mitigation of oxidative stress and apoptosis. In a neuron-like SH-SY5Y model expressing pathogenic mutations, they preserved neurite complexity in a CB2R-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 CB1R-mediated psychoactive effects.
PB American Chemical Society
SN 0022-2623
YR 2025
FD 2025-08-12
LK https://hdl.handle.net/10347/43567
UL https://hdl.handle.net/10347/43567
LA eng
NO Gioé-Gallo, C., Ortigueira, S., Prieto-Díaz, R., Contino, M., Azuaje, J., Perrone, M. G., Riganti, C., Alberga, D., Mangiatordi, G. F., Andújar-Arias, A., García-Rey, A., Graziano, G., Stefanachi, A., Val, C., Martínez, A. L., Rebassa, J. B., Reza, D., Selas, A., Francavilla, F., Paleo, M. R., García-Mera, X., Loza, M. I., Navarro, G., Brea, J., & Sotelo, E. (2025). Conformational Restriction of Designer Drugs Reveals Subtype-Selective and Biased CB2 Agonists with Neuroprotective Effects. Journal of Medicinal Chemistry, 68 (16), 17103–17129. https://doi.org/10.1021/acs.jmedchem.5c00604
NO This work was financially supported by the Consellería de Cultura, Educación e Ordenación Universitaria of the Galician Government: (grant: ED431B 2020/43), Centro Singular de Investigación de Galicia accreditation (2023–2027, ED431G 2023/03) and the European Regional Development Fund (ERDF), Ministerio de Ciencia e Innovación─Agencia Estatal de Investigación-FEDER-UE (PID2020-118511RB-I00, PID2023-146870OB-I00, PID2020-113430RB-I00 and PID2021-124010OB-100), Xunta de Galicia (ED431C 2018/21, ED431C 2022/20 and ED431G 2019/02) and European Regional Development Fund (ERDF) in the frame of the Recovery Assistance for Cohesion and the Territories of Europe (REACT-EU) funds. This research program has been developed in the frame of the European COST action ERNEST (CA 18133).
DS Minerva
RD 25 may 2026