Progress in medicinal chemistry relies heavily on ligands as pharmacologic tools to evaluate selectivity of action, which is particularly relevant to opioid receptors with at least three major types (μ, κ, δ) modulating various physiologic processes. Although highly selective opioid antagonists have been reported for μ and κ receptors, δ receptor antagonists are peptides related to enkephalin, limiting their use in vivo. Here we report the design and structure-selectivity relationship of a series of highly selective and potent non-peptide δ opioid receptor antagonists (1-6). The rationale was based on the "message-address" concept, where the phenyl group of Phe⁴ of leucine-enkephalin acts as both the address and part of the message for δ receptor interaction. We modified naltrexone by attaching a conformationally restricted aromatic ring (indole or benzofuran) to mimic Phe⁴'s phenyl, aiming to bind δ receptor address subsites while sterically hindering binding to other opioid receptors. Indoles 1-5 were synthesized via the Fischer indole synthesis from naltrexone and substituted phenylhydrazines, and benzofuran 6 was obtained with o-phenylhydroxylamine under similar conditions. Testing in the mouse vas deferens (MVD, δ receptor, using [D-Ala²,D-Leu⁵]enkephalin (DADLE)) and guinea pig ileum (GPI, μ with morphine, κ with ethylketazocine) showed compound 1 (naltrindole, NTI) was the most δ-selective, with a K_i of 0.21 nM for δ, 32 nM for μ, and 58 nM for κ (selectivity μ/δ=152, κ/δ=276), over 300 times more potent than the peptide antagonist IC1 174864 (K_i=68 nM). Benzofuran 6 was also δ-selective, suggesting conformational restriction of the benzene ring is key. The N-methyl analogue 8 of NTI was a δ-selective agonist, indicating the orientation of the conformationally fixed aromatic ring contributes to δ selectivity. In conclusion, the "message-address" concept and conformationally fixed non-peptide message and address elements were utilized to design these highly selective and potent δ opioid receptor antagonists. NTI (1) is the first non-peptide highly δ-selective antagonist, which should be a valuable pharmacologic tool for in vivo studies, especially where the blood-brain barrier limits peptide ligand penetration into the CNS.