A chimeric analysis of the opioid receptor domains critical for the binding selectivity of mu opioid ligands.

The mu opioid receptor plays a key role in mediating the physiological, pharmacological, and behavioral effects of endogenous opioids and of opiate drugs such as morphine and heroin. This study examines the structural features critical to the selective binding of mu ligands to the mu receptor as opposed to the other two highly homologous opioid receptors, delta and kappa. We use a series of chimeric constructs between the mu and either the delta or the kappa receptors to investigate the structural bases of binding selectivity of multiple classes of mu-selective ligands. Our results demonstrate that a region comprising the sixth transmembrane domain and the third extracellular loop is critical for the mu/kappa discrimination by all mu-selective ligands. This region is also critical for mu/delta discrimination by the mu antagonists. However, mu agonists, particularly the peptides, exhibit more complex interactions, often relying on the N-terminal region surrounding the first extracellular loop for mu/delta discrimination. Thus, the same mu peptide ligand depends on different parts of the receptor to discriminate between mu and delta receptors on the one hand and mu and kappa on the other. In general, antagonists show the most consistent discrimination mechanisms regardless of construct, whereas agonists, particularly peptides, achieve selectivity by interacting with numerous domains of the receptors.