STRUCTURAL AND ELECTRONIC REQUIREMENTS FOR BINDING AT THE MU-OPIOID RECEPTOR

A pharmacophore for mu-opioid receptor recognition based on a study of the fentanyl class of opioids has recently been characterized in our laboratories. To validate this pharmacophore, we have extended our theoretical studies to include four opiate analogs from structurally different classes and with high affinity but varying selectivity for the mu-opiate receptor. An extensive conformational search of the flexible regions of these compounds has been carried out at two levels of approximations, using the CHARMm force field and the semiempirical molecular orbital method AM1. In a subsequent step, we have determined a series of structural, environmental, and electronic properties for each low-energy conformer of the analogs studied. All four analogs studied can assume a low-energy conformation in which at least three of the four stereoelectronic properties identified as modulators of recognition in the fentanyls are present in the same spatial arrangement. These results provide additional evidence for the plausibility of the proposed pharmacophore for mu-opioid receptor recognition.