3-Deoxyclocinnamox: The first high-affinity, nonpeptide μ-opioid antagonist lacking a phenolic hydroxyl group

The C₃-substituent in morphinan opioids is of critical importance; the 3-OH group is usually associated with very much higher affinity for μ-receptors than H or -OMe. However in this series of 14β-cinnamoylamino derivatives the codeinones (e.g. methoclocinnamox, MC-CAM) had unexpectedly high μ-opioid receptor affinity, similar to that of the morphinone (clocinnamox, C-CAM). The current report relates to the synthesis and in vitro evaluation of deoxyclocinnamox (DOC-CAM) which acted as a high-affinity opioid antagonist similar to C-CAM but with greater μ selectivity. Thus it appears that the C₃-substituent does not play a major role in the binding of the 14β-cinnamoyl series and that the cinnamoyl group itself may in fact be the dominant binding feature.