14 beta-[(p-nitrocinnamoyl)amino]morphinones, 14 beta-[(p-nitrocinnamoyl)amino]-7,8-dihydromorphinones, and their codeinone analogues: synthesis and receptor activity.
A series of 14 beta-[(nitrocinnamoyl)amino]codeinones and morphinones, some of which contain a 5 beta-methyl group, were prepared from 14 beta-aminocodeinones and 14 beta-[N-(cyclopropylmethyl)-amino]norcodeinones. The affinities of the target compounds for the mu, delta, and kappa opioid receptors were determined by radiolabeled binding experiments using bovine brain membranes. An analogous series of 7,8-dihydrocodeinones and morphinones was prepared and assayed in the same systems. The 3-methoxy derivatives 3 and 4 were more selective than the corresponding morphinones for the mu receptor. The 5 beta-methylcodeinones 25 and 27 had lower affinity at all receptors than the corresponding morphinones, but the 5 beta-methylmorphinones had affinities similar to the morphinones 5 and 6. A similar pattern was observed in the 7,8-dihydro series. Two compounds, 5 beta-methyl-14 beta-[(p-nitrocinnamoyl)amino]-7,8-dihydromorphinone, 20 (MET-CAMO), and N-(cyclopropylmethyl)-14 beta-[(p-nitrocinnamoyl)amino]-7,8-dihydronormorphinone, 22 (N-CPM-MET- CAMO), acted as nonequilibrium ligands in antinociception and membrane binding studies. In mice after icv administration, neither ligand showed any agonist activity but 8-24 h after administration both compounds acted as potent mu antagonists. A Scatchard plot of the effect of N-CPM-MET-CAMO on [3H]DAMGO ([3H]D-Ala2, (Me)-Phe4, Gly(ol)5] enkephalin) binding to bovine striatal membranes showed that there was a significant decrease in the Bmax value and a marginal effect on the Kd value suggesting that the number of binding sites was reduced. When taken together, these results support the view that 20 and 22 bind covalently to the mu receptor. On the other hand, when N-acetylcysteine and 22 were allowed to react in a buffered solution, 22 was recovered unchanged. Under these conditions no Michael reaction was observed.
Sebastian
A
A
Department of Chemistry, Rensselaer Polytechnic Institute, Troy, New York 12180.
Bidlack
J M
JM
Jiang
Q
Q
Deecher
D
D
Teitler
M
M
Glick
S D
SD
Archer
S
S
D000818:Animals; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D002417:Cattle; D002934:Cinnamates / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D003061:Codeine / Q000031:analogs & derivatives; D004091:Hydromorphone / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D011957:Receptors, Opioid / Q000187:drug effects* / Q000378:metabolism; D013329:Structure-Activity Relationship
D002934:Cinnamates; D011957:Receptors, Opioid; C036083:morphinone; D004091:Hydromorphone; D003061:Codeine