@article {Hjorth1089, author = {S A Hjorth and K Thirstrup and D K Grandy and T W Schwartz}, title = {Analysis of selective binding epitopes for the kappa-opioid receptor antagonist nor-binaltorphimine.}, volume = {47}, number = {6}, pages = {1089--1094}, year = {1995}, publisher = {American Society for Pharmacology and Experimental Therapeutics}, abstract = {The structural determinants for the selective binding of the nonpeptide opioid receptor antagonist nor-binaltorphimine (nor-BNI) to the kappa-opioid receptor were characterized using a systematic series of chimeras between the kappa receptor and the homologous mu-opioid receptor. All 10 chimeric constructs bound the nonselective antagonists (-)-naloxone and diprenorphine with similar affinities, as did the two wild-type receptors. Introduction of amino-terminal segments of increasing length, extending to and including transmembrane segment VI, from the mu receptor into the kappa receptor did not impair the high affinity binding of nor-BNI, and neither did introduction of the intracellular carboxyl-terminal extension of the mu receptor. In contrast, nor-BNI binding was impaired \> or = 600-fold in constructs in which extracellular loop 3 and transmembrane segment VII originated from the mu receptor. The exchange of a single residue within this region, Glu297, for lysine, the corresponding residue from the mu receptor, reduced the binding affinity of nor-BNI 142-fold, without affecting the binding the nonselective compounds (-)-naloxone and diprenorphine. It is concluded that the selective binding of nor-BNI to the kappa-opioid receptor is determined by nonconserved residues located in extracellular loop 3 and transmembrane segment VII and that Glu297, located just outside transmembrane segment VI, plays a major role in the kappa-selective binding characteristics of nor-BNI.}, issn = {0026-895X}, URL = {https://molpharm.aspetjournals.org/content/47/6/1089}, eprint = {https://molpharm.aspetjournals.org/content/47/6/1089.full.pdf}, journal = {Molecular Pharmacology} }