Molecular mechanics and 1H NMR conformational study of 3,8-diazabicyclo[3,2,1] octanes and related cis-2,6-dimethylpiperazines active on opioid receptors

3-Trans-cinnanyl-8-propionyl-3,8-diazabicyclo[3,2,1]octane 1, its monocyclic analog 4-trans-cinnamyl-1-propionyl-cis-2,6-dimethylpiperazine 2 and their isomers having the nitrogen sustituents exchanged, 3 and 4, have been submitted to conformational analysis by molecular mechanics and 1H NMR spectroscopy. The results of molecular modeling indicate that, while the monocyclic compound 2 has a preferred conformation very similar to the corresponding bicyclic compound 1, compound 4 is quite different with respect to 3; it is the only compound with equatorially oriented substituents on the carbon atoms of the hexacyclic ring. This feature could explain the low affinity of 4 towards μ receptors, as compared with the high affinity of 1-3.