Integrated pharmacological and structural profiling reveals CB1 residue interaction patterns associated with synthetic cannabinoid receptor agonist efficacy

Background and Purpose: Among new psychoactive substances, synthetic cannabinoid receptor agonists (SCRAs) encompass considerable structural diversity and show wide variation in cannabinoid receptor 1 (CB1) potency and efficacy, but the molecular and receptor-interaction characteristics underlying these differences remain unclear. We assessed the pharmacological profiles of 16 SCRAs and examined structural features associated with differences in CB1 potency and efficacy. Experimental Approach: CB1 agonist activity was measured in a CB1-G15-based Ca2+ assay, and cataleptic effects were assessed in mice. Ligand-receptor interactions were characterized by molecular docking to an active-state CB1 structure. Principal component analysis (PCA) was applied to residue-level interaction profiles, and the resulting scores were tested for associations with CB1 potency and efficacy. Key Results: Potency and efficacy varied widely across cellular and animal assays, with several SCRAs exhibiting different pharmacological responses across the two experimental systems. PCA identified an interaction pattern whose PC1 scores were significantly associated with Emax but not EC50, with contributions from activation-related CB1 residues including the PHE200-TRP356 toggle switch. Molecular descriptor analysis likewise identified structural features significantly associated with in vitro and in vivo Emax. Conclusion and Implications: Our findings suggest that CB1 efficacy is associated with distinct receptor-interaction patterns among structurally diverse SCRAs. Combining functional pharmacology with receptor-level interaction analysis provides structural insight into SCRA efficacy and may help prioritize emerging compounds for further pharmacological and behavioral evaluation.