DAMGO, A MU-OPIOID RECEPTOR-SELECTIVE AGONIST, DISTINGUISHES BETWEEN MU-OPIOID AND DELTA-OPIOID RECEPTORS AROUND THEIR FIRST EXTRACELLULAR LOOPS

The structural basis of mu-opioid receptor (OPR) for the specificity i n its ligand binding was investigated using chimeric mu/delta-OPRs. Re placement of the region around the first extracellular loop of delta-O PR with the corresponding region of mu-OPR gave the resultant chimeric receptor the similar affinity to DAMGO compared with the native mu-OP R. The reciprocal replacement deprived the high affinity to DAMGO from mu-OPR. These results indicate that the difference(s) in the structur e around the first extracellular loop is critical for DAMGO to disting uish between mu- and delta-OPRs. Furthermore, displacement studies rev ealed that this region is partly involved in the discrimination betwee n mu- and delta-OPRs by other peptidic mu-selective ligands, such as d ermorphin, morphiceptin and CTOP, but not by non-peptidic ligands, suc h as morphine and naloxone.