Long-Acting Opiate Agonists and Antagonists: 14-Hydroxydihydromorphinone Hydrazones

Article abstract of DOI:10.1021/jm00180a019

Two new long-acting hydrazone derivatives of 14-hydroxydihydromorphinones have been synthesized, oxymorphazone and naltrexazone.Both derivatives show high affinity for opiate binding sites in vitro, similar to naloxazone, the hydrazone analogue of naloxone.Sodium and manganese shifts imply that naltrexazone, like naloxazone, is a pure antagonist.By contrast, oxymorphazone inhibition of receptor binding is dramatically reduced by sodium and potentiated by manganese, suggesting it is an agonist.When given in vivo, all agents produce a significant inhibition of receptor binding for over 24 h despite extensive washing of the brain homogenates.Oxymorphone, naltrexone, and naloxone are without effect.Twenty-four hours after in vivo administration of oxymorphazone, 82percent of mice are still analgetic compared to only 17percent of oxymorphone-treated mice (p < 0.005).Twenty-four hours after naltrexazone or naloxazone treatment all mice were protected from morphine analgesia (12 mg/kg; p < 0.005), while naltrexone- and naloxone-treated animals did not differ significantly from saline-treated controls.