14-O-Cinnamoyl esters of naltrexone (6) were synthesized and evaluated in isolated tissue assays in vitro and in vivo in mouse antinociceptive assays. Their predominant opioid receptor activity was mu receptor (MOR) antagonism, but the unsubstituted cinnamoyl derivative (6a) had partial MOR agonist activity in vitro and in vivo. When compared to the equivalent 14-cinnamoylaminomorphinones (5), the cinnamoyloxy morphinones (6) as MOR antagonists had a shorter duration of action and were less effective as pseudoirreversible antagonists. The antinociceptive activity of the cinnamoyloxycodeinones (7) was not significantly greater than that of the morphinones (6), but they exhibited no evidence of any pseudoirreversible MOR antagonism. In both respects, these profiles differed from those of the equivalent 14-cinnamoylaminocodeinones (4).
Moynihan, H., Jales, A. R., Greedy, B. M., Rennison, D., Broadbear, J. H., Purington, L., ... Husbands, S. M. (2009). 14β-O-cinnamoylnaltrexone and related dihydrocodeinones are mu opioid receptor partial agonists with predominant antagonist activity. Journal of Medicinal Chemistry, 52(6), 1553-1557. https://doi.org/10.1021/jm8012272