On the basis of previous structure-activity studies of the highly potent and selective δ-opioid receptor antagonist naltrindole (1) and the spiroindanyl analagues 2 and 3, we have synthesized epimeric pairs of spirobenzocyclohexyl derivatives of naltrexone, oxymorphone, and hydromorphone (4-9). Pharmacologic evaluation in smooth muscle assays has revealed that the oxymorphone derivatives (6, 7) are δ-selective agonists and possess receptor binding profiles that are consistent with their agonist activity. It is proposed that the spirobenzocyclohexyl group of 6 and 7 orients its benzene moiety orthogonally with respect to the C ring of the opiate in a manner similar to that of the spiroindanyl analogue 3. It is suggested that this orthogonal orientation serves as an 'address' to facilitate activation of δ receptors. The finding that the hydromorphone analagues (8, 9) were full μ agonists and exhibited only partial δ agonist activity suggests that the 14-hydroxyl group also contributes to the δ agonist activity. The naltrexone derivatives (4, 5) were μ-selective antagonists and exhibited relatively weak δ antagonist activity. However, the binding data indicated a very high-affinity δ-selective binding profile that was not consistent with the pharmacology. This study illustrates the differential contributions of the δ 'address' to agonist and antagonist activity and supports the idea of different recognition sites for interaction of agonist and antagonist ligands with δ-opioid receptors.