Cinnamoyl derivatives of 7alpha-aminomethyl-6,14-endo-ethanotetrahydrothebaine and 7alpha-aminomethyl-6,14-endo-ethanotetrahydrooripavine and related opioid ligands.

A new series of ligands has been synthesized where the cinnamoyl group of the 14-cinnamoylamino morphinones has been introduced to the 7alpha-substituent of the 6,14-bridged oripavine series. In vitro the compounds were mostly low efficacy partial agonists or antagonists with some selectivity for the mu opioid receptor, with evidence of micro efficacy in vivo. The similarity in SAR between these 6,14-bridged oripavines and the 14-cinnamoylamino series suggests a similar mode of interaction with the micro opioid receptor.

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

In investigation of the effects of 14-substitution in the indolomorphinan series of delta-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 delta-selectivity, 4b had high kappa-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 kappa-opioid receptor binding motif.