14-BETA-[(P-NITROCINNAMOYL)AMINO]MORPHINONES, -[(P-NITROCINNAMOYL)AMINO]-7,8-DIHYDROMORPHINONES, AND THEIR CODEINONE ANALOGS - SYNTHESIS AND RECEPTOR ACTIVITY

A series of 14beta-[(nitrocinnamoyl)amino]codeinones and morphinones, some of which contain a 5beta-Methyl group, were prepared from 14beta- aminocodeinones and 14beta-[N-(cyclopropylmethyl)-amino]norcodeinones. The affinities of the target compounds for the mu, delta, and kappa o pioid receptors were determined by radiolabeled binding experiments us ing bovine brain membranes. An analogous series of 7,8-dihydrocodeinon es and morphinones was prepared and assayed in the same systems. The 3 -methoxy derivatives 3 and 4 were more selective than the correspondin g morphinones for the mu receptor. The 5beta-methylcodeinones 25 and 2 7 had lower affinity at all receptors than the corresponding morphinon es, but the 5beta-methylmorphinones had affinities similar to the morp hinones 5 and 6. A similar pattern was observed in the 7,8-dihydro ser ies. Two compounds, a-[(p-nitrocinnamoyl)amino]-7,8-dihydromorphinone, 20 (MET-CAMO), and (p-nitrocinnamoyl)amino]-7,8-dihydronormorphinone, 22 (N-CPM-MET-CAMO), acted as nonequilibrium ligands in antinocicepti on and membrane binding studies. In mice after icv administration, nei ther ligand showed any agonist activity but 8-24 h after administratio n both compounds acted as potent mu antagonists. A Scatchard plot of t he effect of N-CPM-MET-CAMO on [H-3]DAMGO ([H-3]D-Ala2, (Me)-Phe4, Gly (ol)5]enkephalin) binding to bovine striatal membranes showed that the re was a significant decrease in the B(max) value and a marginal effec t on the K(d) value suggesting that the number of binding sites was re duced. When taken together, these results support the view that 20 and 22 bind covalently to the mu receptor. On the other hand, when N-acet ylcysteine and 22 were allowed to react in a buffered solution, 22 was recovered unchanged. Under these conditions no Michael reaction was o bserved.