Bremazocine Recognizes the Difference in Four Amino Acid Residues to Discriminate Between a Nociceptin/Orphanin FQ Receptor and Opioid Receptors

Abstract

We investigated the molecular basis of the discrimination between nociceptin/orphanin FQ receptor (NociR) and opioid receptors (OPRs) by bremazocine, a non-type-selective opioid ligand. Construction of several chimeric receptors between NociR and κ-opioid receptor (KOPR) and mutant NociRs followed by binding experiments with [³H]bremazocine showed that the mutation of only four amino acid residues of NociR, Ala²¹⁶, Val²⁷⁹, Gln²⁸⁰ and Val²⁸¹, to the amino acid residues located at the corresponding position of KOPR, Lys²²⁷, Ile²⁹⁰, His²⁹¹ and Ile²⁹², made it possible for the resultant mutant NociR to bind bremazocine with high affinity. Considering that these four amino acid residues are conserved among μ-, δ- and κ-OPRs, the present result suggests that bremazocine recognizes the difference in these four amino acid residues to discriminate between NociR and OPRs.