The δ-selective opioid antagonist naltrindole (NTI), as well as the κ-selective opioid antagonists norbinaltorphimine (norBNI) and 5′-guanidinonaltrindole (GNTI), are derived from naltrexone, a universal opioid antagonist. Previous studies have indicated that extracellular loop III is the key region for discrimination by naltrexone-derived selective ligands between the δ, μ, and κ opioid receptor types. It has been proposed that selective ligands could bind to all three receptor types if the appropriate portions of the extracellular loops were eliminated. To investigate this possibility, several single-point mutant opioid receptors have been generated with the aim of conferring enhanced affinity of selective ligands for their nonpreferred receptor types. Mutations were made in all three types of opioid receptors with the focus on two positions at the extracellular end of transmembrane regions (TM) VI and VII. It was found that the δ-selective NTI could bind both μ and κ receptors with significantly enhanced affinity when an aromatic residue in TM VII was replaced with alanine (μ[W318A] and κ[Y312A]). Similarly, κ-selective antagonists, norBNI and GNTI, showed enhanced affinity for the μ[W318A] mutant and for both μ and δ receptors when a glutamate residue was incorporated into the extracellular end of TM VI (μ[K303E] and δ[W284E]). These results demonstrate that naltrexone-derived selective ligands achieve their selectivity via a combination of enhanced affinity of the address for a particular subsite along with loss of affinity due to steric interference at nonpreferred types. The results reveal key residues in the 'address' recognition locus that contribute to the selectivity of opioid ligands and support the hypothesis that recognition of the naltrexone moiety is essentially the same for all three receptor types.