dihydromorphine and naloxonazine

In addition to morphine-selective mu 2 and enkephalin-preferring delta sites, recent evidence supports the presence within the central nervous system of a common site with very high affinity for both enkephalins and opiates termed the mu 1 site. This concept of a common, very high affinity site for multiple neurotransmitters is a unique concept in neuropharmacology, differing from classical transmitter systems which possess multiple receptor classes for a single transmitter. This review will address both the biochemical and pharmacological evidence supporting the existence of this site.

Topics: Aging; Analgesia; Animals; Autoradiography; Binding, Competitive; Brain; Dihydromorphine; Endorphins; Enkephalin, Leucine; Enkephalin, Leucine-2-Alanine; Enkephalins; Ethylmaleimide; Morphine; Naloxone; Neurotransmitter Agents; Phylogeny; Receptors, Opioid; Receptors, Opioid, mu; Respiration; Substance-Related Disorders; Tissue Distribution

Small modifications of the basic structure of phencyclidine have produced compounds with potent opioid analgesic actions. Detailed competition studies show that two of these phencyclidine derivatives, the 3'-hydroxy and the 4-phenyl-4-hydroxy analogs, displace 3H-opioid binding in a multiphasic manner. Approximately 25% of the total specific binding of all the radiolabeled opioids is displaced by low concentrations of the derivatives while the remainder of the binding is far less sensitive. The inclusion of these derivatives in saturation studies with [3H]dihydromorphine indicate that both compounds interact with highest affinity with mu1 sites. Furthermore, the prior in vivo administration of naloxonazine 24 h earlier reduces the analgesic potency of the 4-phenyl-4-hydroxy compound by 63% supporting a mu1 mechanism of action.

Topics: Analgesics; Animals; Binding, Competitive; Dihydromorphine; Male; Naloxone; Phencyclidine; Rats; Rats, Inbred Strains; Receptors, Opioid; Receptors, Opioid, mu

Mr2034 has been proposed as a kappa opiate. While Mr2034 inhibited the binding of the kappa opiate 3H-ethylketocyclazocine better than unlabeled ethylketocyclazocine, it also displaced the binding of 3H-dihydromorphine and 3H-SKF 10047 more potently than morphine and SKF 10047, respectively. 3H-D-ala2-D-leu5-enkephalin was displaced equally well by Mr2034 and D-ala2-D-leu5-enkephalin. Saturation studies of 3H-Mr2034 binding demonstrated curvilinear Scatchard plots which could be dissected into two components by computer: KD1 0.06 nM, Bmax1 2.49 fmoles/mg tissue; and KD2 2.4 nM, Bmax2 6.57 fmoles/mg tissue. A portion of the higher affinity (KD 0.06 nM) component was inhibited by naloxonazine treatment in vitro (50 nM), suggesting that 3H-Mr2034 bound with very high affinity to mu1 sites. Displacement of 3H-Mr2034 binding by opioids was multiphasic, again implying that 3H-Mr2034 was binding to more than one class, of site. In view of its similar potency in inhibiting mu (3H-dihydromorphine), kappa (3H-ethylketocycla-zocine), sigma (3H-SKF 10047) and delta (3H-D-ala2-D-leu5-enkephalin) opioids Mr2034 might be considered a universal opiate.

Topics: Animals; Benzomorphans; Brain; Cyclazocine; Dihydromorphine; Enkephalin, Leucine; Enkephalin, Leucine-2-Alanine; Ethylketocyclazocine; Male; Morphinans; Naloxone; Phenazocine; Rats; Rats, Inbred Strains; Receptors, Opioid

The ability of morphine to inhibit the electrically induced contractions of the guinea pig ileum is mediated through the mu class of opioid receptors. However, recent studies have implied the existence of two subtypes of mu receptors in the brain (mu1 and mu2), which differ both biochemically and pharmacologically. The antagonist naloxonazine and the agonist oxymorphonazine selectively and irreversibly bind mu1 sites. Treatment of both rat and guinea pig brain homogenates with naloxonazine in vitro to selectively inhibit mu1 binding significantly decreased [3H]dihydromorphine binding, whereas binding in similarly treated guinea pig ileum longitudinal muscle-myenteric plexus was virtually unaffected (P less than 0.0005). Similarly, the actions of both drugs in the guinea pig ileum contraction assay were reversible. The findings imply that morphine's actions on the guinea pig ileum were mediated through the mu2 subtype of opioid receptor.

Topics: Animals; Brain; Brain Chemistry; Dihydromorphine; Guinea Pigs; Ileum; In Vitro Techniques; Myenteric Plexus; Naloxone; Oxymorphone; Receptors, Opioid; Receptors, Opioid, mu

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