Fig 3. Piperidine rigidity influences both affinity and selectivity.

a, N-aniline-piperidine connecting dihedral free energy landscapes. S2 dihedral occupancy for fentanyl, carfentanil, and lofentanil was calculated to be 38.5%, 43.4%, and 75.9% respectfully. b, Superposition of lofentanil’s optimal S2 dihedral conformation with low-energy conformations identified in mABP ligand binding simulations. c, Comparison of μOR, 𝛿OR, κOR orthosteric site amino acid compositions and selectivity structural analysis. d, Correlation between S2 dihedral propensity with in-vitro potencies taken from ref [30].