A series consisting of spiroindanyl (5-7), benzospiroindanyl (8-10), and spiroperinaphthyl (11) derivatives of naltrexone and oxymorphone were synthesized in order to investigate the role of an orthogonal-oriented 'address' for δ opioid receptors. All of the ligands exhibited a preference for δ receptors in vitro. The 7-benzospiroindanyl derivative 8 (BSINTX) was the most selective δ opioid receptor antagonist in vitro. In mice BSINTX antagonized the δ1-selective agonist, [D-Pen2,D-Pen5]enkephalin without significantly affecting the antinociceptive potency of δ2, μ, and κ agonists. The results of this study are consistent with an orthogonally- oriented address favoring δ1 activity.