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.
