Compounds that bind with significant affinity to the opioid receptor types, delta, mu, and kappa, with different combinations of activation and inhibition at these three receptors could be promising behaviorally selective agents. Working on this hypothesis, the chemical moieties common to three different sets of opioid receptor agonists with significant affinity for each of the three receptor types delta, mu, or kappa were identified. Using a distance analysis approach, common geometric arrangements of these chemical moieties were found for selected delta, mu, or kappa opioid agonists. The chemical and geometric commonalities among agonists at each opioid receptor type were then compared with a non-specific opioid recognition pharmacophore recently developed. The comparison provided identification of the additional requirements for activation of delta, mu, and kappa opioid receptors. The distance analysis approach was able to clearly discriminate kappa-agonists, while global molecular properties for all compounds were calculated to identify additional requirements for activation of delta and mu receptors. Comparisons of the combined geometric and physicochemical properties calculated for each of the three sets of agonists allowed the determination of unique requirements for activation of each of the three opioid receptors. These results can be used to improve the activation selectivity of known opioid agonists and as a guide for the identification of novel selective opioid ligands with potential therapeutic usefulness.