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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↗
PubMed2004

Characterization of the complex morphinan derivative BU72 as a high efficacy, long-lasting mu-opioid receptor agonist.

The development of buprenorphine as a treatment for opiate abuse and dependence has drawn attention to opioid ligands that have agonist actions followed by long-lasting antagonist actions. In a search for alternatives to buprenorphine, we discovered a bridged pyrrolidinomorphinan (BU72). In vitro, BU72 displayed high affinity and efficacy for mu-opioid receptors, but was also a partial delta-opioid receptor agonist and a full kappa-opioid receptor agonist. BU72 was a highly potent and long-lasting antinociceptive agent against both thermal and chemical nociception in the mouse and against thermal nociception in the monkey. These effects were prevented by mu-, but not kappa- or delta-, opioid receptor antagonists. Once the agonist effects of BU72 had subsided, the compound acted to attenuate the antinociceptive action of morphine. BU72 is too efficacious for human use but manipulation to reduce efficacy could provide a lead to the development of a treatment for opioid dependence.

Analgesics↗
PubMed2004

1,2-Dehydroreticuline synthase, the branch point enzyme opening the morphinan biosynthetic pathway.

A synthase which oxidizes (S)-reticuline to 1,2-dehydroreticuline has been found to occur in seedlings of opium poppy (Papaver somniferum L.). Due to its instability, this enzyme could only be partly purified (ca. 5-fold enrichment). Partial characterization at this stage of purification showed that it does not need a redox cofactor and accepts both (S)-reticuline and (S)-norreticuline as substrates. [1-(2)H, (13)C]-(R,S)-reticuline was enzymatically converted into [1-(13)C]-dehydroreticuline, which has been identified by mass spectrometry. Release of the hydrogen atom in position C-1 of the isoquinoline alkaloid during the oxidative conversion, was exploited as a sensitive assay system for this enzyme. The enzyme has a pH optimum of 8.75, a temperature optimum of 37 degrees C and the apparent K(M) value for the substrate reticuline was shown to be 117 microM. Moreover it could be demonstrated by sucrose density gradient centrifugation that the enzyme is located in vesicles of varying size. In combination with the previously discovered strictly stereoselective and NADPH dependent 1,2-dehydroreticuline reductase the detection of this enzyme, the 1,2-dehydroreticuline synthase, provides the necessary inversion of configuration and completes the pathway from two molecules of L-tyrosine via (S)-norcoclaurine to (R)-reticuline in opium poppy involving a total number of 11 enzymes.

Alkaloids↗
PubMed2003

Synthesis, opioid receptor binding, and functional activity of 5'-substituted 17-cyclopropylmethylpyrido[2',3':6,7]morphinans.

A series of naltrexone-derived pyridomorphinans possessing various substituents at the 5'-position on the pyridine ring were synthesized and evaluated for opioid receptor binding in rodent brain membranes and functional activity in smooth muscle preparations. While the introduction of aromatic 1-pyrrolyl group (6h) improved the delta affinity and delta antagonist potency of the parent compound (3), the introduction of guanidine group (6i) transformed it to a kappa selective ligand in opioid receptor binding and [35S]GTP-gamma-S functional assays.

Animals↗
PubMed1973

Lethality of the morphinan isomers levorphanol and dextrorphan.

Significantly different (P<0.05) LD(50) values were found in Swiss-Webster mice for levorphanol (73 mg/kg, i.p.) and dextrorphan (120 mg/kg, i.p.). A subcutaneous injection of naloxone 15 min before challenge prevented the lethal effect of an LD(98) of levorphanol, with ED(50) value of 1.36 mg/kg. Naloxone, in doses from 2 to 100 mg/kg, did not prevent death caused by 150 mg/kg of either dextrorphan or levorphanol. Levorphanol was lethal for mice pretreated with 10 mg/kg of naloxone, a dose sufficient to block opiate-specific lethal effects, but the LD(50) value was 109 mg/kg, in contrast to 73 mg/kg in the absence of naloxone. By the criteria of stereospecificity and naloxone blockade, levorphanol-induced mortality in mice is a typical opiate effect in the lower of the two dose ranges studied. At higher doses of levorphanol a non-specific effect supervenes, with an LD(50) value virtually the same as that of dextrorphan.

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↗