INTERACTION OF BRIDGED PIPERAZINE DERIVATIVES WITH THE μ-OPIOID RECEPTOR — A THEORETICAL MODEL

The flexible molecular docking was used to study interactions between a series of 3,6-diazabicyclo[3.1.1]heptanes, 9,10-diazatricyclo[4.2.1.1]decanes, and 2,7-diazatricyclo [4.4.0.0]decanes N-substituted by propanoyl and by arylalkenyl groups, and a model of the μ-opioid receptor. It has been found that the optimal position and orientation of the compounds in the ligand–receptor complex resemble that of fentanyl analogs described earlier.1 This model explains stereochemical effects on binding of the two series of 3,6-diazabicyclo[3.1.1]heptanes, suggesting that the steric interaction of the bridge methylenic group plays the major role in modulating μ-receptor affinity of those molecules. Ab initio B3LYP method was used to determine electrostatic potentials of different bridged piperazine derivatives, and to estimate electrostatic contribution to the ligand–receptor complex stability.