ABSTRACT
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).
Subject(s)
Hydrocodone/pharmacology , Naltrexone/analogs & derivatives , Receptors, Opioid, mu/agonists , Receptors, Opioid, mu/antagonists & inhibitors , Magnetic Resonance Spectroscopy , Naltrexone/pharmacology , Spectrometry, Mass, Electrospray IonizationABSTRACT
The study of kappa-opioid receptor function in vivo has been hampered by the limited choice of selective kappa-antagonists. Recently discovered kappa-antagonists have not yet been utilised in vivo. We here report the synthesis and in vitro evaluation of a new amidine derivative of naltrindole. It showed substantially greater kappa-selectivity in binding assays than known analogues with shorter spacer in the amidine side chain. This indicates that in nor-BNI and related selective kappa-antagonists, the second basic centre may not be ideally located.
