A series of naltrindole-related ligands (4-10) with an N-methyl, N-phenethyl, N-cinnamyl, or an unsubstituted basic nitrogen were synthesized and tested for opioid agonist and antagonist activity in smooth muscle preparations and in mice. The nor compounds (4 and 6) and the phenethyl derivatives (5 and 8) displayed full agonist activity (IC50 = 85-179 nM) in the mouse vas deferens preparation (MVD) while the other members of the series exhibited partial agonist or weak antagonist activity. In the guinea pig ileum preparation (GPI), all compounds except 8 were partial agonists. The ligands that were evaluated in mice were found to produce antinociception that was not selectively mediated via δ opioid receptors. However, two of these ligands (4 and 5) appeared to be δ-selective opioid receptor antagonists at subthreshold doses for antinociception. The finding that all of the compounds bind selectively to δ opioid receptors in guinea pig brain membranes together with the in vitro pharmacology and in vivo antagonist studies suggests that the lack of δ agonist selectivity in vivo may be due to a number of factors, including a basic difference between the δ receptor system in the MVD and in the mouse brain. Further, it is suggested that the constellation of message and address components in the morphindole nucleus may tend to stabilize δ receptors in the brain in an antagonist state.