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

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

SUBMITTER: Gioe-Gallo C 

PROVIDER: S-EPMC12406204 | biostudies-literature | 2025 Aug

REPOSITORIES: biostudies-literature