Morphinans metabolism

Dibenz[h,e]azepine-6,11-diones ent-Morphinan nomenclature, 1, 29 Morphinan, 1,2,3,4-tetrahydro-nomenclature, 1, 29 14-a-Morphinan, N-methyl-synthesis, 1, 480 Morphinans nomenclature, 1, 29 as pharmaceuticals, 1, 148 synthesis, 2, 377 Morphine, 2, 512 as analgesic, 1, 167 as metabolite of normorphine, 1, 235 as pharmaceutical, 1, 146, 147, 148 synthesis, 1, 480 Morphine alkaloids structure, 4, 534 Morphin-7-en nomenclature, 1, 29 Morphinone, dihydro-as pharmaceutical, 1, 147 Morpholine — see also 1,4-Oxazine, tetrahydrocarcinogenicity, 1, 229 corrosion inhibitor, 1, 409 metabolism, 1, 226 nomenclature, 3, 996 structure, 2, 5 synthesis, 2, 89 Morpholine, 4-aciyloyl-polymers, 1, 291 Morpholine, alkenyl-polymers, 1, 291... 

The cytochrome P450 responsible for the oxidation of (S)-N-methylcoclaurine to (S)-3 -hydroxy-N-methylcocluarine has been overexpressed in opium poppy plants, and morphinan alkaloid production in the latex is increased subsequently to 4.5 times the level in wild-type plants (58). Additionally, suppression of this enzyme resulted in a decrease in morphinan alkaloids to 16% of the wild-type level. Notably, analysis of a variety of biosynthetic gene transcript levels in these experiments supports the hypothesis that this P450 enzyme plays a regulatory role in the biosynthesis of benzylisoquinoline alkaloids. Collectively, these studies highlight that the complex metabolic networks found in plants are not redirected easily or predictably in all cases. 

Takemori AE, Mannering GJ. 1958. Metabolic N- and O-demethylation of morphine- and morphinan-type analgesics. J. Pharmacol. Exp. Therap. 123 171-79... 

TRK-851 is a clinical candidate for an antitussive drug it has a novel, complex morphinan ring system. The development of TRK-851 was motivated by the finding that NTI, a selective 8 opioid receptor antagonist, showed antitussive effect. In this section we will describe the process of developing TRK-851, including the structure-activity relationship (SAR) studies on NTI derivatives and the difficulties encountered in overcoming a defect in the metabolism of a prototype clinical candidate, TRK-850. 

A/-Methyl morphinan was the first such compound tested and is only 20 per cent as active as morphine, but since the phenolic group is missing, this is not surprising. The more relevant levorphanol structure is five times more active than morphine and, although side-effects are also increased, levorphanol has a massive advantage over morphine in that it can be taken orally and lasts much longer in the body. This is because levorphanol is not metabolized in the liver to the same extent as morphine. 

The levo isomers of 3-hydroxy-Af-methyl-morphinan and of methadone are demethylated by rat liver two to three times more rapidly than the corresponding dextro antipodes. The S(-l-)-enantiomer of hexobarbital (Fig. 17.4) is metabolized almost twice as rapidly as the R(— )-enantio-mer by allylic hydroxylation and, in the dog, the dextrorotatory isomer of 5-ethyl-5-phenyl-hydantoin affords ten times more p-hydroxy-metabolite than the levorotatory isomer. Hydroxylation takes place alpha to a carbonyl in the dextrorotary enantiomer of glutathimide, whereas the... 

Secondary metabolism is a form of differentiation, but cells grown in vitro are rapidly dividing, undifferentiated cells. Only at the end of the growth phase of batch-cultured cells may some form of differentiation occur, connected with the production of secondary metabolites. A plant produces a wide variety of secondary metabolites, all with different, mostly unknown functions. In in vitro cultured cells those compounds which defend the plant against microorganisms, namely, phytoalexins, are often easily formed. For example. Cinchona cell cultures produce large amounts of anthraquinones, but the alkaloids of interest, the quinolines, are produced in trace amounts only. Similarly Papaver cell cultures produce sanguinarine and closely related alkaloids, but no morphinane alkaloids. 

Callus tissue of P. somniferum has been reported not to produce morphinan alkaloids but benzophenanthridine, protopine, and aporphine bases. Recent experiments have shown that (5)-reticuline from (R,S)-reticuline (41) administered to tissue cultures was transformed into (5)-scoulerine (52) and (5)-cheilan-thifoline (53) [(R)-reticuline was recovered unchanged]. Morphine, codeine, and thebaine were not metabolized by the culture but (—)-codeinone (48) was converted stereospecifically and in high yield into (—)-codeine (50), both by the culture and by a crude enzyme preparation from it. 

Despite the detection of COR and other known morphinan branch pathway enzymes in opium poppy cell cultures (63-65,67), morphine and codeine are not produced. The inability of cultured cells to accumulate morphine might reflect the absence of other relevant enzymes or structural proteins that preclude the formation of a requisite metabolic channel. Nevertheless, the efficient operation of the sang-uinarine pathway indicates that cultured opium poppy cells possess the essential regulatory, eellular, and metabolic components to support the biosynthesis and... 

Recently, opium poppy (P. somniferum) has emerged as a model system to investigate alkaloid metabolism. Great progress towards the elucidation of BIA metabolism including the well-known morphinan alkaloids has been made at the biochemical and molecular levels and a restricted number of enzyme families have been implicated. 

Allen RS et al (2008) Metabolic engineering of morphinan alkaloids by over-expression and RNAi suppressirai of salutaridinol 7-0-acetyltransferase in opium poppy. Plant Biotechnol J... 

The existence of a metabolic channel wonld be in line with the regnlatory independence of the enzymes of the morphinane branch from the general benzylisoqninohne biosynthesis. A well known expression of this phenomenon is the intimate link between lacticifer development and biosynthesis of morphine dedifferentiated, cultured cells of opium poppy do not prodnce... 

Allen RS, Miller JAC, Chitty JA, et al. (2008) Metabolic engineering of morphinan alkaloids by over-expression and RNAi suppression of salutaridinol7-0-acetyltransferase in opium poppy. Plant Biotech J 6 22-30 Allen RS, Millgate AG, Chitty JA, et al. (2004) RNAi-mediated replacement of morphine with the noimarcotic alkaloid reticuline in opium poppy. Nature Biotech 22 1559-1568 AmaimM, Wanner G,ZenkMH (1986) Intracellular compartmentation of two enzymes of berberine biosynthesis in plant cell cultures. Planta 167 310-320... 

Coutts IGC, Hamblin MR, Tinley EJ (1979) The enzymatic oxidation of phenolic tetrahydroiso-quinoline-1-carboxylic acids. J Chem Soc Perkin Trans 1 2744-2750 Davis VE, Cashaw JL, McMurtrey KD, Ruchirawat S, Nimit Y (1982) Metabolism of tetrahydro-isoquinolines and related alkaloids. In Bloom F, Barchas J, Sandler M, Usdin E (eds) Beta-carbolines and tetrahydroisoquinolines. Liss, New York, p 99 Furuya T, Nakano M, Yoshikawa T (1978) Biotransformation of (RS)-reticuline and morphinan alkaloids by cell cultures of Papaver somniferum. Phytochemistry 17 891-893 Gates M (1953) Conversion of codeinone to codeine. J Am Chem Soc 75 4340-4341 Graves JMH, Smith WK (1967) Transformation of pregnenolone and progesterone by cultured plant cells. Nature (London) 214 124 8-1249... 

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