14-amino, 14-alkylamino, and 14-acylamino analogs of oxymorphindole. Differential effects on opioid receptor binding and functional profiles.

The 14-amino analogue of oxymorphindole (OMI) was synthesized and found to possess delta-opioid binding affinity and selectivity similar to OMI. Substitution of the amino group with alkyl, arylalkyl, and acyl groups had relatively little effect on delta-affinity but delta-selectivity was reduced. In functional assays the 14-phenylacetylamino derivative 6d was a selective delta-agonist whereas the phenethylamino analogue 5d was a mu-agonist and low efficacy delta partial agonist that warrants further investigation as an analgesic with low tolerance and dependence.

The role of the side chain in determining relative delta- and kappa-affinity in C5'-substituted analogues of naltrindole.

The role of the side chain in 5'-substituted analogues of naltrindole has been further explored with the synthesis of series of amides, amidines, and ureas. Amidines (8, 13) had greatest selectivity for the kappa receptor, as predicted from consideration of the message-address concept. It was also found that an appropriately located carbonyl group, in ureas (10) and amides (7), led to retention of affinity and antagonist potency at the delta receptor.