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At least 19 recordsLinked to original sources
PubMed1988

Morphinans attenuate cortical neuronal injury induced by glucose deprivation in vitro.

The non-narcotic dextrorotatory morphinan, dextrorphan, as well as its levorotatory opioid enantiomer, levorphanol, and its O-methyl derivative, dextromethorphan, have recently been shown to antagonize N-methyl-D-aspartate receptor-mediated neurotoxicity. Consistent with in vivo data suggesting that this neurotoxicity contributes to the neuronal damage associated with hypoglycemia, micromolar concentrations of these morphinans markedly attenuated the injury of cultured mouse cortical neurons produced by acute glucose deprivation. These observations lend specific support to the possibility that morphinan compounds may prove to have clinical therapeutic utility in hypoglycemic encephalopathy.

Animals↗
PubMedDate not supplied

Differential effects of morphinan drugs on haloperidol-induced catalepsy in rats: a comparative study with an N-methyl-D-aspartate antagonist.

The effects of the morphinan drugs dextrorphan, dextromethorphan and levorphanol were tested towards the cataleptic activity induced by 1 mg/kg of haloperidol i.p. in rats. The influence of the morphinans was compared to that of the N-methyl-D-aspartate competitive antagonist, 2-amino-5-phosphonovaleric acid. 2-Amino-5-phosphonovaleric acid (0.5 mumoles, i.c.v.), dextrorphan (7.5-15 mg/kg, i.p.) and dextromethorphan (15-30 mg/kg, i.p.) significantly reduced the degree of catalepsy in the haloperidol-treated rats within 15 min. Conversely, levorphanol (15-30 mg/kg, i.p.) significantly increased the degree of catalepsy in the haloperidol-treated rats within 15 min. Naloxone (2 mg/kg, i.p.) counteracted the potentiating effects of levorphanol. These findings demonstrate a differential influence of the morphinan stereoisomers dextrorphan and levorphanol on experimental catalepsy, and suggest a potential use of dextromethorphan in the treatment of Parkinson's disease.

2-Amino-5-phosphonovalerate↗
PubMed1991

Diversified electrophysiological properties of morphinan drugs in rats.

1. In in vivo and in vitro studies in rats, the effects of dextromethorphan (DM), dextrorphan (DX), and levorphanol (LV) were compared with those induced by kappa and sigma opiate agonists. 2. In rat hippocampal slices all the morphinans were able to pertubate the CAI hippocampal synaptic transmission, while only DX and LV affected the N-methyl-D-aspartate excitability through a possible interaction at sigma opiate receptors. 3. On the other hand EEG studies show that only DX appears to act as a full agonist at sigma opiate receptors. 4. Present data demonstrate diversified electrophysiological properties of morphinans both in in vitro and in vivo studies.

Animals↗
PubMed1992

Replenishment of brain adenosine triphosphate content by morphinan-type N-methyl-D-asparatate receptor antagonists, dextrorphan and dextromethorphan through the activation of adenylate kinase.

The in vitro effects of four N-methyl-D-aspartate (NMDA) receptor antagonists, dextrorphan, (DX, CAS 125-73-5), dextromethorphan, (DM, CAS 125-71-3), dizocilpine (CAS 77086-21-6) and (+/-) 2-amino-7-phosphonoheptanoate (AP-7, CAS 85797-13-3) on rat brain adenylate kinase (AK) have been studied. DM was the most active of the four compounds in increasing rat brain AK activity. DX was slightly less active than DM, while the most potent NMDA antagonist, dizocilpine was somewhat weaker than the above two morphinan analogs (DX and DM). For AP-7, the AK activity was unchanged. The results may indicate that a causal relation cannot be made between the activation of the AK by these compounds and their ability to act as NMDA antagonists. When DX was added, the Km and Vmax values of the enzyme for ADP as a substrate decreased and increased, respectively, possibly reflecting an affinity change for the enzyme-substrate interaction by DX. The observed increase in the AK activity by the morphinan-type NMDA antagonists in vitro might result in their preserving effects on cerebral neuron integrity under the conditions where cerebral energy metabolism is disturbed. This assumption was at least partly confirmed in in vivo tests in which DX, unlike dizocilpine, increased ATP content of the brain in mice under the influence of hypoxia exerted by i.v. injection of KCN.

2-Amino-5-phosphonovalerate↗
PubMed1991

Neurobehavioral evidence for kappa agonist activity of the morphinan derivative 14-beta-methyl 8-oxacyclorphan [BC (3016)].

The purpose of the present study was to determine if the in vivo neurobehavioral effects of the morphinan 14-beta-methyl 8-oxacyclorphan, [BC (3016)], would reflect the kappa agonist activity found in our previous in vitro studies. The effects of intracisternal administration of various doses (10-80 micrograms) of BC (3016) on body temperature, muscle rigidity, nociception of thermal, chemical and mechanical stimuli as well as its ability to induce catalepsy were examined. The effects of intrathecal administration of the same doses of the compound on reactivity of animals to a thermal stimulus were also assessed. Finally, the ability of BC (3016) to antagonize well known neurobehavioral effects of morphine was investigated. Results indicate that the analgesic properties of BC (3016) resemble those of typical kappa agonists: Intracisternal administration of the drug failed to affect nociception to an aversive thermal stimulus but markedly reduced the reactivity of animals subjected to noxious chemical or mechanical stimuli. On the other hand, intrathecal administration of BC (3016) significantly attenuated nociception of animals to a thermal stimulus. The in vivo neurobehavioral effects of BC (3016) appear to be kappa selective since the drug did not decrease body temperature, increase muscular tone or induce catalepsy, three effects generally attributed to mu agonists. Furthermore, BC (3016) antagonized the immobility, trunk rigidity, catalepsy and analgesia induced by morphine. In summary, the present results reveal that BC (3016) displays a profile of neurobehavioral effects similar to that of well known kappa agonists.

Animals↗
PubMed1991

Irreversible blockade of the high and low affinity (3H) naloxone binding sites by C-6 derivatives of morphinane-6-ones.

C-6 derivatives--hydrazones, phenylhydrazones, dinitrophenylhydrazones, oximes and semicarbazones--of morphinane-6-ones were synthesized and their binding characteristics were studied on rat brain membranes. The dihydromorphinone and oxymorphone derivatives compete for the (3H)naloxone binding sites with high affinity, while the dihydrocodeinone and oxycodone derivatives are less potent. The affinity of the new compounds is decreased for the delta sites as compared to the parent ligands. The ligands bearing bulky substituents also bind with low affinity to the kappa sites. The modification decreased the Na(+)-index of compounds indicating their mixed agonist-antagonist character. The dihydromorphinone derivatives are all capable to block irreversibly the high affinity binding site of (3H)naloxone, whereas the dihydrocodeionone derivatives block irreversibly the low affinity site. A possible mechanism for the inhibition is suggested.

Affinity Labels↗
PubMed1989

Isolation of a novel morphinan 3-O-diglucuronide metabolite from dog urine.

Following oral administration of the narcotic antagonist nalmefene [17-(cyclopropylmethyl)-4,5 alpha-epoxy-6-methylenemorphinan-3,14-diol] labeled with 14C to the dog, approximately 50% of the dose was excreted in the urine as a highly polar water-soluble conjugate. Although this major metabolite could be hydrolyzed with beta-glucuronidase to yield nalmefene, the intact conjugate was chromatographically more polar on reversed-phase high-performance liquid chromatography (HPLC) than authentic nalmefene 3-O-glucuronide. Milligram quantities of the metabolite were subsequently isolated and subjected to fast atom bombardment (FAB) mass spectral and nuclear magnetic resonance (NMR) analyses. The conjugate was identified as nalmefene 3-O-beta-diglucuronide with a 1,2-beta linkage between the two glucuronic acids. It is unlikely that this novel form of conjugate is unique to nalmefene and it is probably a metabolite of other morphinans and/or similar drugs in the dog. Nalmefene 3-O-diglucuronide is not a metabolite of nalmefene in man.

Animals↗
PubMed1992

Inhibitory influence of morphinans on ictal and interictal EEG changes induced by cortical application of penicillin in rabbits: a comparative study with NMDA antagonists and pentobarbitone.

The effects of dextrorphan (DX) and dextromethorphan (DM) were tested using the electroencephalogram (EEG) and behavioral effects induced by topical cortical application of penicillin in rabbits. For comparison, the influence of the NMDA antagonists, dizocilpine (MK 801) and 3-((+-(-)2-carboxypiperazine-4-yl)propyl-1-phosphonic acid (CPP), and of pentobarbitone was investigated. Intracortical injection of 500 IU of penicillin produced an EEG spiking followed by a repeated generalization of the electrical and behavioral symptoms. Within a few minutes, DX (5-15 mg/kg, IV) or pentobarbitone (5-10 mg/kg, IV) reduced dose dependently and significantly (p less than 0.01) the interictal and ictal EEG and behavioral effects elicited by cortical injection of 500 IU of penicillin. Higher doses of pentobarbitone (20 mg/kg, IV) but not of DX (20 mg/kg, IV) completely blocked the ictal behavioral and EEG effects elicited by cortical injection of 500 IU of penicillin. Within a few minutes, MK 801 (0.1-0.2 mg/kg, IV) or CPP (10-20 mg/kg, IV) reduced dose dependently and significantly (p less than 0.01) the ictal EEG and behavioral effects elicited by cortical injection of 500 IU of penicillin, while they did not affect the penicillin-induced interictal EEG changes. Higher doses of MK 801 (0.3 mg/kg, IV) completely blocked the ictal behavioral and EEG effects elicited by cortical injection of 500 IU of penicillin. Within a few minutes, DM (10-20 mg/kg, IV) blocked the behavioral effects, but failed to affect either the interictal or the ictal EEG effects induced by cortical injection of 500 IU of penicillin.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1986

14-beta-Methyl-8-oxacyclorphan (BC-3016), a morphinan derivative with high affinity for kappa opioid receptor: comparison with dynorphin-A(1-13).

14-beta-Methyl-8-oxacyclorphan (BC-3016) was tested for its ability to depress the electrically evoked contractions of the guinea pig ileum (GPI) and of the mouse vas deferens (MVD) and to compete with the binding of prototype ligands selective for kappa-, mu-, or delta-opioid receptors in membrane preparations of rat brain and guinea pig cerebellum. BC-3016 was a very potent agonist in the GPI and MVD preparations, with ID50 of 0.7 and 31 nM, respectively. The activity of levorphanol, a standard alkaloid related to BC-3016, was much lower in both assays with ID50 values of 44 and 86 nM, respectively. Conversely, the activity of BC-3016 was quite comparable to that of dynorphin-A(1-13) in both preparations. In the GPI assay, a putative kappa-receptor antagonist, MR-2266, was 6.6 and 5.5 times more potent than naloxone in blocking the activity of BC-3016 and dynorphin-A(1-13), respectively. BC-3016 was also very potent in displacing bound [3H]ethylketocyclazocine ([3H]EKC) to membrane preparations of the guinea pig cerebellum, a brain component containing predominantly kappa-opioid receptors (Ki of 0.58 nM). Its potency in the displacement of the bound mu-ligand, 3H-labelled (D-Ala2,MePhe4,Gly-OH5)-enkephalin ([3H]DAGO), to rat brain homogenates was somewhat lower (Ki of 0.8 nM) but still high when compared with its ability to displace the delta-ligand, 3H-labelled (D-Ser2, Thr6)-Leu-enkephalin ([3H]DSLET) to rat brain homogenates (Ki of 4.45 nM). The affinity of BC-3016 for the opioid receptor was 2.1-fold higher than that of U-50488H, a selective kappa-opioid ligand.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1989

Synthesis and analgetic activity of sulfur-containing morphinans and related compounds.

3-Acylthiomorphinans, 3-carbamoylthio-3-deoxydihydromorphine and 3-benzoylthio-9-aza-17-carbamorphinan were synthesized by Newman-Kwart rearrangement of the corresponding O-thiocarbamates. The analgetic activities were lower than that of pentazocine, and the opioid receptor binding affinities were very weak. These acylthiomorphinans showed low antinociceptive activity compared with corresponding sulfur-containing benzomorphans. 3-Carbamoylthio-deoxydihydromorphine had no significant analgetic activity.

Analgesics↗
PubMed1987

Effect of several d-morphinans on ascites tumors in mice.

Dextromethorphan and its analogues (DM 16, DM 34, DM 72, DM 75 and DM 96) were examined for their effect on Ehrlich ascites carcinoma or ascites sarcoma-180 in female mice of the ddY strain. The suspension of Ehrlich carcinoma cells or sarcoma-180 cells was prepared from mice at 10 days after i.p. inoculation of the cells, using Hanks' balanced salt solution, and the cell suspension was inoculated i.p. into mice (2 X 10(6) viable cells/mouse). The chemicals dissolved in physiological saline containing 5% HCO-60 were then injected i.p. into the mice once daily for 5 successive days (5-40 mg/kg/day). In addition, mice given the tumor cells were treated with the saline containing 5% HCO-60 alone for 5 days (untreated mice). In groups of mice bearing Ehrlich ascites carcinoma or ascites sarcoma-180, the mean survival time of mice treated with 20-40 mg/kg/day of DM 96 was more than twice that of the corresponding untreated mice. The mean survival time of mice treated with 20 mg/kg/day of DM 96 was also longer than that of mice treated with 40 mg/kg/day of the other chemicals, irrespective of the ascites tumors. Concerning these survival times, the LD50 (i.p.) of DM 96 in mice differed slightly from that of other chemicals (88 mg/kg and 77-106 mg/kg). These results indicate that DM 96 is more active than the other chemicals against the ascites tumors in mice.

Animals↗