DAMGO, a μ‐opioid receptor selective ligand, distinguishes between μ‐and κ‐opioid receptors at a different region from that for the distinction between μ‐ and δ‐opioid receptors

Abstract

The structural basis of opioid receptors (OPRs) for the subtype‐selective binding of DAMGO, a μ‐opioid receptor selective ligand, was investigated using chimeric μ/κ‐OPRs. Replacement of the region from the middle of the fifth transmembrane domain to the C‐terminal of μ‐OPR with the corresponding region of μ‐OPR remarkably decreased the binding affinity to DAMGO, while the reciprocal chimera revealed the high affinity to DAMGO. These results indicate that DAMGO distinguishes between μ‐ and μ‐OPRs at the region around the third extracellular loop, different from the case of the distinction between μ‐and δ‐OPRs in which the region around the first extracellular loop is important. Furthermore, displacement studies revealed that the region around the third extracellular loop is involved in the discrimination between μ‐ and κ‐OPRs not only by peptidic μ‐ selective ligands but also by non‐peptidic ligands, such as morphine and naloxone.