N-benzylnaltrindoles as long-acting delta-opioid receptor antagonists

The indolic nitrogen of the delta-opioid receptor antagonist, naltrindole (1), was derivatized with benzyl or substituted benzyl to afford a series (2-9) that retained delta-opioid receptor antagonist activity and selectivity in vitro. The two most potent members (2 and 8) of the series were evaluated in mice and were found to produce delta-selective antagonism of [D-Ser2,Leu5]enkephalin-Thr6 which lasted 5 days. N-Benzylnaltrindole (2) should be useful as a delta 2-selective antagonist for in vivo studies where prolonged action is desired.