Structural determinants of opioid activity in derivatives of 14-aminomorphinones: Effect of substitution in the aromatic ring of cinnamoylaminomorphinones and codeinones

In recent years there has been substantial interest in the 14-aminodihydromorphinone derivatives methoclocinnamox (MC-CAM) and clocinnamox (C-CAM). To investigate the importance of the cinnamoyl ring substituent, a series of analogues have been prepared with chloro, methyl, and nitro substituents in the 2′ and 4′ positions. Despite some discrepancies between the in vitro and in vivo data, a clear SAR could be observed where the 2′-chloro and 2′-methyl ligands consistently displayed higher efficacy than their 4′-substituted analogues. The new series also followed the well-established SAR that 17-methyl ligands have greater efficacy at the μ opioid receptor than their 17-cyclopropylmethyl counterparts.