Opioid binding and in vitro profiles of a series of 4-hydroxy-3-methoxyindolomorphinans. Transformation of a δ-selective ligand into a high affinity κ-selective ligand by introduction of a 5,14-substituted bridge

In investigation of the effects of 14-substitution in the indolomorphinan series of δ-selective opioid ligands, 5,14-bridged indolomorphinans (4) were prepared from the equivalent dihydrothebainone acid-catalyzed rearrangement products of the dihydrothevinols. Though the new ligands generally had low affinity for opioid receptors and no δ-selectivity, 4b had high κ-affinity and substantial selectivity which was also seen in the precursor morphinanone (3b). This indicates that the methylbenzylidene-substituted bridge in these compounds is a dominant κ-opioid receptor binding motif.