Molecular mechanics energy minimization and electrostatic potential surface calculations have been used to examine a series of opioid compounds that interact with the µ opoid receptor and a recently discovered high-affinity naloxone binding site (the λ site). The compounds studied include members of the morphinan, 4,5-epoxymorphinan, and benzomorphan families. All compounds bind with a high affinity at the µ opiate receptor site, but only the 4,5-epoxymorphinans bind tightly at the λ site. The results suggest that conformational differences in the various families do not satisfactorily explain the observed trends in binding affinity at the λ site. However, electrostatic potential surfaces for a representative subset of these opioids exhibit patterns that allow us to classify members as high-affinity or low-affinity λ-site ligands in good agreement with the experimental results. The procedures used in this work may be useful in defining characteristics that impart selectivity for opiate receptor subtypes such as the µ, δ, and κ receptors.