COMPUTER-AIDED STRUCTURE AFFINITY RELATIONSHIPS IN A SET OF PIPERAZINE AND 3,8-DIAZABICYCLO[3.2.1]OCTANE DERIVATIVES BINDING TO THE MU-OPIOID RECEPTOR

Molecular modeling studies were carried out on a set of piperazine and 3,8-diazabicyclo[3.2.1]octane derivatives with the aim to highlight t he main factors modulating their affinity for the mu-opioid receptor. Structure-affinity relationships were developed with the aid of molecu lar mechanics and semiempirical quantum-mechanics methods. According t o our proposed pharmacodynamic model, the binding to the mu-receptor i s promoted by the following physico-chemical features: the presence of hydrocarbon fragments on the nitrogen ring frame capable of interacti ng with one of two hypothesized hydrophobic receptor pockets; a 'corre ct' orientation of an N-propionyl side chain so as to avoid a sterical ly hindered region of the receptor; the possibility of accepting a hyd rogen bond from a receptor site complementary to the morphine phenol o xygen.