In view of previous studies indicating that the irreversible properties of opiate azines such as naloxonazine are not due to a bivalent mechanism, we have synthesized a series of opiate hydrazones. In standard competition assays which measure both reversible and irreversible inhibition of binding, the hydrazone derivatives lowered radiolabeled opioid binding almost as well as naloxone and oxymorphone. However, the phenylhydrazone derivatives produced a profound wash-resistant inhibition of binding. The similar potencies of the methylhydrazine and phenylhydrazine derivatives in standard competition studies contrasted significantly with their effectiveness in eliciting wash-resistant inhibition of binding, suggesting the importance of the phenyl group in the production of wash-resistant inhibition. The p-nitrophenyl hydrazones were the most effective wash-irreversible inhibitors. Although oxymorphonazine does not irreversibly inhibit radiolabeled opioid binding as effectively as naloxonazine or naltrexonazine, the oxymorphone phenylhydrazones were as potent as their corresponding naloxone compounds. Incubation of [3H]naloxone-p-nitrophenylhydrazone with albumin demonstrated significant incorporation of radiolabel into the protein after sodium dodecylsulfate gel electrophoresis. This suggests that the phenylhydrazones have significant reactivities toward proteins and might produce their irreversible actions through covalent interactions.