2. Academic Validation
  3. Conformational Restriction of Designer Drugs Reveals Subtype-Selective and Biased CB2 Agonists with Neuroprotective Effects

Conformational Restriction of Designer Drugs Reveals Subtype-Selective and Biased CB2 Agonists with Neuroprotective Effects

  • J Med Chem. 2025 Aug 28;68(16):17103-17129. doi: 10.1021/acs.jmedchem.5c00604.
Claudia Gioé-Gallo 1,  Sandra Ortigueira 1,  Rubén Prieto-Díaz 1,  Marialessandra Contino 2,  Jhonny Azuaje 1,  Maria Grazia Perrone 2,  Chiara Riganti 3,  Domenico Alberga 4,  Giuseppe Felice Mangiatordi 4,  Antonio Andújar-Arias 1,  Aitor García-Rey 1,  Giovanni Graziano 1,  Angela Stefanachi 2,  Cristina Val 5,  Antón Leandro Martínez 5,  Joan Biel Rebassa 6,  David Reza 1,  Asier Selas 1,  Fabio Francavilla 1,  M Rita Paleo 1,  Xerardo García-Mera 1,  M Isabel Loza 5,  Gemma Navarro 6,  José Brea 5,  Eddy Sotelo 1
Affiliations

Affiliations

  • 1 Centro Singular de Investigación en Química Biolóxica y Materiais Moleculares (CIQUS), Universidade de Santiago de Compostela, 15782 Santiago de Compostela, Spain.
  • 2 Dipartimento di Farmacia-Scienze del Farmaco, Università degli Studi di Bari ALDO MORO, via Orabona 4, 70125 Bari, Italy.
  • 3 Dipartimento di Oncologia, Università degli Studi di Torino, piazza Nizza 44, 10126 Torino, Italy.
  • 4 CNR - Institute of Crystallography, Via Giovanni Amendola, 122/O, 70126 Bari, Italy.
  • 5 Centro Singular de Investigación en Medicina Molecular y Enfermedades Crónicas (CIMUS), Universidade de Santiago de Compostela, 15782 Santiago de Compostela, Spain.
  • 6 Department of Biochemistry and Physiology, School of Pharmacy and Food Science, Universitat de Barcelona, Institut de Neurosciències UB, Barcelona 08028, Spain.
PMID: 40796509 DOI: 10.1021/acs.jmedchem.5c00604
Abstract

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.

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