A series of amino acid conjugates (2-6) of naltrindole (1) were synthesized from 7′-carboxynaltrindole (7) in order to obtain ô antagonists that would have minimal access to the central nervous system (CNS) upon peripheral administration. All of the ligands (2-7) were tested in smooth muscle preparations and found to be potent and selective ô opioid antagonists. Receptor binding showed 2-7 to be highly δ-selective, with Ki ratios (μ/δ, κ/δ) ranging from 127 to 38 000. Two of the more selective conjugates, the glycinate 2 and aspartate 3, were evaluated by the iv and icv routes in mice, and they afforded very high iv/icv dose ratios (112 766 and 46 667, respectively) consistent with poor CNS penetration. The in vivo testing revealed that 2 and 3 are δ1-selective antagonists, in contrast to naltriben and related ligands which are δ2-selective. The fact that the binding data are not consistent with the in vivo data suggests that the origin of the selectivity of naltrindole congeners may be related to selective access to tissue compartments in the CNS rather than to binding affinity differences between δ opioid receptor subtypes.