Conformational analysis of 6α- and 6β-naltrexol and derivatives and relationship to opioid receptor affinity.

Naltrexol and its C₆ α and β desoxy, iodo, mesyl, tosyl, trifyl, dimethylcarbamyl, and diphenylcarbamyl derivatives were studied in their energy-minimized C ring chair-like and boat-like conformations using B3LYP/6-31G** and SM5.4/A to estimate aqueous solvation free energy. The results were compared to experimental opioid receptor binding affinities. The total energy difference between β conformers correlated well with MOR binding affinity, while the aqueous solvation free energy correlated well with the KOR binding affinity.