Naltrindole (1) (NTI) is a highly potent and selective δ-opioid receptor antagonist. In an effort to understand the origin of the high potency, affinity, and selectivity of NTI, we have examined the conformational role of its indolic benzene moiety through the synthesis of related naltrexone derivatives 3–8, which contain the benzene moiety in different orientations and at different attachments in the molecule. One of these naltrexone derivatives, 5, whose 7-indanyl benzene moiety is orthogonal to ring C of the morphinan system, is a potent δ-opioid receptor antagonist in vitro and in vivo. Computer-assisted molecular overlay studies of the minimized structures (2–8) revealed the importance of the position of the benzene moiety for effective interaction with δ-opioid receptors. In compounds 2, 4, and 5, the aromatic ring falls in the same region of space as that of the indolic benzene moiety of NTI, and all of these ligands possessed significant activity at δ-opioid receptors. Analogues (3 and 6–8) which were shown to have relatively weak δ-opioid receptor antagonist potency have their aromatic groups located in a space that is different from that of the more potent analogues.