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Titolo:
OXIDATION CHEMISTRY OF L-4-YL]OXY]-[3-(2-AMINO-2-CARBOXYETHYL)]-1H-INDOLE - A PUTATIVE ABERRANT METABOLITE OF 5-HYDROXYTRYPTOPHAN
Autore:
WU Z; SHEN XM; DRYHURST G;
Indirizzi:
UNIV OKLAHOMA,DEPT CHEM & BIOCHEM NORMAN OK 73019 UNIV OKLAHOMA,DEPT CHEM & BIOCHEM NORMAN OK 73019
Titolo Testata:
Bioorganic chemistry
fascicolo: 3, volume: 23, anno: 1995,
pagine: 227 - 255
SICI:
0045-2068(1995)23:3<227:OCOL>2.0.ZU;2-A
Fonte:
ISI
Lingua:
ENG
Soggetto:
ALZHEIMERS-DISEASE; RAT-BRAIN; ELECTROCHEMICAL OXIDATION; BIOCHEMICAL ASSESSMENT; ENZYMATIC OXIDATION; FOREBRAIN ISCHEMIA; PHYSIOLOGICAL PH; NEURONAL DAMAGE; 5-HT1 RECEPTOR; FREE-RADICALS;
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Science Citation Index Expanded
Science Citation Index Expanded
Citazioni:
53
Recensione:
Indirizzi per estratti:
Citazione:
Z. Wu et al., "OXIDATION CHEMISTRY OF L-4-YL]OXY]-[3-(2-AMINO-2-CARBOXYETHYL)]-1H-INDOLE - A PUTATIVE ABERRANT METABOLITE OF 5-HYDROXYTRYPTOPHAN", Bioorganic chemistry, 23(3), 1995, pp. 227-255

Abstract

Oxidative damage is known to occur in certain regions of the brain ina number of neurodegenerative disorders that include Alzheimer's Disease (AD) and transient cerebral ischemia and as a result of methamphetamine abuse. Furthermore, aberrant but unknown oxidized forms of 5-hydroxytryptophan (5-HTPP) and 5-hydroxytryptamine (5-HT) have been detected in the cerebrospinal fluid (CSF) of AD patients but not in that ofage-matched controls. Accordingly, it is possible that aberrant oxidative metabolites of 5-HTPP and 5-HT might play roles in the neurodegenerative processes that occur in the AD brain and other neurodegenerative disorders. Previous studies have established that the title compound (1) is among the products of the electrochemically driven and various enzyme-mediated oxidations of 5-HTPP. This investigation has focusedon both the electrochemical and peroxidase-mediated oxidations of 1 at physiological pH and has established that this dimer is significantly more easily oxidized than 5-HTPP from which it is derived. Under weakly oxidizing conditions 1 is oxidized via a putative carbocation intermediate to an equimolar mixture of 5-HTPP and tryptophan-4,5-dione (2). Under more strongly oxidizing conditions further oxidation of 5-HTPP gives a C(4)-centered carbocation intermediate that can react with the free hydroxyl residue of 1 to form a trimer, tetramer, and larger oligomers that are subsequently further oxidized ultimately to dione 2. When administered into the brains of mice, 1 is a remarkably lethal compound (LD(50) = 3.3 mu g) and evokes a hyperactivity syndrome. Analyses of the brains of mice during this behavioral response reveal that an acute dose of 1 evokes a significant decrease of norepinephrine (NE) levels. Only minor alterations in whole brain levels of DA and 5-HT occur but levels of 3,4-dihydroxyphenylacetic acid, homovanillic acid,and 5-hydroxyindole-3-acetic acid are significantly elevated. These results suggest that the hyperactivity syndrome evoked by 1 is related to the elevated release and turnover of NE, DA, and 5-HT. Based upon the results obtained and by comparison with other pharmacologic manipulations that evoke a similar hyperactivity syndrome in mice and rats itappears that 1 might be metabolized in vivo to metabolites that interact with certain 5-HT and perhaps other receptor subpopulations. (C) 1995 Academic Press, Inc.

ASDD Area Sistemi Dipartimentali e Documentali, Università di Bologna, Catalogo delle riviste ed altri periodici
Documento generato il 05/12/20 alle ore 19:48:47