Oxidation chemistry and biochemistry of the central mammalian alkaloid 1-methyl-6-hydroxy-1,2,3,4-tetrahydro-beta-carboline.
The electrochemical oxidation of the central mammalian alkaloid 1-methyl-6-hydroxy-1,2,3,4-tetrahydro-beta-carboline (1) has been studied in neutral aqueous solution at a pyrolytic graphite electrode (PGE). Voltammograms of 1 show two closely spaced oxidation peaks, Ia and IIa. At potentials less positive than the peak potential (Ep) for peak Ia, 1 is oxidized to a radical intermediate which dimerizes to give two diastereomers of 5,5'-bi(1-methyl-6-hydroxy-1,2,3,4-tetrahydro-beta-carboline) (5 and 6). At potentials more positive than Ep for peak Ia the putative radical intermediate is further electrooxidized to a C(5)-centered carbocation which reacts with 1 in an ion-substrate reaction to give 5 and 6 or with water to give, ultimately, 1-methyl-1,2,3,4-tetrahydro-beta-carboline-5,6-dione (12). Dimers 5 and 6 give two reversible oxidation peaks at the PGE, the second of which corresponds to peak IIa observed in voltammograms of 1. Because 5 and 6 are easily oxidizable compounds they are only observed as products in the initial stages of the controlled potential electrooxidation of 1. Tyrosinase/O2, human ceruloplasmin/O2, and peroxidase/H2O2 also oxidize 1 to 5, 6, and 12 as the initial products. In the presence of glutathione the electrochemically driven and enzyme-mediated oxidations of 1 result in the formation of 5-S-glutathionyl-1-methyl-6-hydroxy-1,2,3,4-tetrahydro-beta-carboline as a major product. Central administration of diastereomer 5 or 6 to mice evoked behavioral responses similar to those caused by the opioid analgesics. These behavioral effects, which include spatial disorientation and a characteristic ducklike walk, became most pronounced approximately 3 h after drug administration and continued for about 3 days. Neurotransmitter and related metabolite analyses of whole brain reveal that 5 and 6 cause a general increase in dopaminergic and serotonergic activity and a small but significant decrease in cholinergic activity. These transmitter/metabolite disturbances appear to parallel the time course of the observed behavioral effects. The possible roles of in vivo oxidations of 1, an alkaloid which is elevated in mammalian brain following ethanol consumption, in the addictive, behavioral, and neurodegenerative consequences of chronic alcoholism are discussed.
Zhang
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Department of Chemistry and Biochemistry, University of Oklahoma, Norman 73019-0370.
Goyal
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Blank
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Dryhurst
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D000470:Alkaloids / Q000737:chemistry; D000818:Animals; D001921:Brain / Q000187:drug effects; D002243:Carbolines / Q000138:chemical synthesis* / Q000737:chemistry* / Q000494:pharmacology / Q000633:toxicity; D004563:Electrochemistry; D007928:Lethal Dose 50; D051379:Mice; D010084:Oxidation-Reduction; D011458:Prostaglandins E / Q000378:metabolism
D000470:Alkaloids; D002243:Carbolines; D011458:Prostaglandins E; C035602:6-hydroxy-1-methyltryptoline