For the rational design of ligands for opioid receptors, attempts to analyze the ligand-receptor interactions were made. Some morphine derivatives were designed as molecular probes for the affinity labeling of opioid receptors. The combination of the results of the affinity labeling and the 3D models of the opioid receptors lead to the prediction of models of morphine derivatives in complex with the opioid receptors, and the modes of binding in the opioid receptor subtypes were hypothesized. As an application of using the predicted binding mode for the rational drug design of morphine derivatives, a k-agonist, 10-oxo derivative of N-cyclopropylmethyl (-)-6-b-acetylthio-dihydronormorphine (KT-95) was designed based on the hypothesis, and the results of biological characterization of KT-95 were found to support the hypothesis. The unique pharmacological profiles of KT-95 as potential clinical analgesic are also summarized.
Keywords: Opioid Receptor, k-Opioid Receptor, Euphoria, Dysphoria, N-cyclopropylmethyl (-)-6-b-acetylthio-dihydronormorphine, cAMP, inositol 1,4,5-trisphosphate, G protein coupled receptors (GPCRs), CoMFA