DAMGO, A MU-OPIOID RECEPTOR-SELECTIVE LIGAND, DISTINGUISHES BETWEEN MU-OPIOID AND KAPPA-OPIOID RECEPTORS AT A DIFFERENT REGION FROM THAT FOR THE DISTINCTION BETWEEN MU-OPIOID AND DELTA-OPIOID RECEPTORS

The structural basis of opioid receptors (OPRs) for the subtype-select ive binding of DAMGO, a mu-opioid receptor selective ligand, was inves tigated using chimeric mu/kappa-OPRs. Replacement of the region from t he middle of the fifth transmembrane domain to the C-terminal of mu-OP R with the corresponding region of mu-OPR remarkably decreased the bin ding affinity to DAMGO, while the reciprocal chimera revealed the high affinity to DAMGO. These results indicate that DAMGO distinguishes be tween mu- and mu-OPRs at the region around the third extracellular loo p, different from the case of the distinction between mu-and delta-OPR s in which the region around the first extracellular loop is important . Furthermore, displacement studies revealed that the region around th e third extracellular loop is involved in the discrimination between m u- and kappa-OPRs not only by peptidic mu- selective ligands but also by non-peptidic ligands, such as morphine and naloxone.