naltrexazone and oxymorphazone

Further investigations into the molecular actions of the 14-hydroxydihydromorphinone hydrazones (naloxazone, oxymorphazone, and naltrexazone) have suggested that their irreversible actions can be explained by the formation of their azines. These azines, naloxonazine, naltrexonazine, and oxymorphonazine, irreversibly block opiate binding in vitro 20- to 40-fold more potently than their corresponding hydrozones, naloxazone, naltrexazone, and oxymorphazone. The blockade of binding by naloxonazine shows the same selectivity for high affinity, or mu1, sites as naloxazone.

Topics: Animals; Brain; Cell Membrane; Dihydromorphine; Drug Stability; Hydromorphone; Kinetics; Naloxone; Naltrexone; Oxymorphone; Receptors, Opioid; Structure-Activity Relationship

Differences in the receptor mechanisms of opiate analgesia and respiratory depression have been studied with three novel irreversible opiates. A single injection of the irreversible agonist oxymorphazone produces analgesia in mice, lasting over 24 hours. Conversely, the irreversible antagonist naloxazone dramatically reduces the analgesic effectiveness of a variety of opiate alkaloids and enkephalin analogs for over a day. Despite this marked reduction in analgesia after naloxazone treatment, morphine lethality (LD50) is unchanged in similarly treated mice. Receptor binding studies show that naloxazone irreversibly and selectively blocks a subpopulation of opiate receptors (the mu1 sites) to which all classes of opiates and enkephalins bind with highest affinity, whereas the drug has little to no effect on their lower-affinity sites (mu, and delta). The return of high-affinity receptor (mu1) binding to normal levels corresponds closely to the return of analgesic sensitivity and possibly represents receptor turnover in the central nervous system. These studies suggest that both opiate and opioid peptide analgesia is mediated through a single receptor subpopulation distinct from those involved with respiratory depression, and raise the possibility of specific opiate analgesics without respiratory depression.

Topics: Analgesia; Animals; Humans; Lethal Dose 50; Morphine; Muridae; Naloxone; Naltrexone; Oxymorphone; Receptors, Opioid; Respiration; Respiratory Insufficiency