Synthetic cannabinoid receptor agonists (SCRAs) 4F-MDMB-BINACA, 4F-MDMB-BICA, and 5F-MDMB-PICA share a “tail” group but differ in indazole/indole cores and N-fluoroalkyl chain lengths (C4 vs. C5). However, the impact of these structural variations on cannabimimetic potency and the influence of the inhalational abuse route remain unclear. This study integrated behavioural profiling, receptor binding analysis, and pharmacokinetic modelling to address these gaps. ICR mice were administered the three SCRAs via inhalation or intraperitoneal (i.p.) injection, and cannabinoid “tetrad effects” (analgesia, hypothermia, catalepsy, locomotor suppression) were quantified. Surface plasmon resonance (SPR) was used to determine CB₁/CB₂ receptor binding specificities, while physiologically based pharmacokinetic (PBPK) models predicted tissue/brain distribution. Results showed that after i.p. administration, the ED₅₀ rank for tetrad effects of four cannabinoid tetrad effects was 5F-MDMB-PICA ≈ 4F-MDMB-BINACA <4F-MDMB-BICA, consistent with CB₁ affinity (K_D: 7.772 × 10⁻⁶, 8.468 × 10⁻⁵, and 7.599 × 10⁻⁵ M, respectively). Inhalation reversed the hierarchy for analgesia and hypothermia to 5F-MDMB-PICA <4F-MDMB-BICA <4F-MDMB-BINACA, with 4F-MDMB-BICA showing enhanced relative potency that offsets its lower CB₁ affinity. ADMET predictions indicated 5F-MDMB-PICA had the highest risk score, with greater lipophilicity, longer half-life, and extensive brain accumulation. These findings demonstrate that minimal structural changes and administration route profoundly alter SCRAs potency, refining structure-activity relationships and informing route-specific risk assessment strategies.