Oxidation Chemistry of 5-[[3-(2-Amino-2-carboxyethyl)-5-hydroxy-1H-indol-4-yl]oxy]-[3-(2-amino-2-carboxyethyl)]-1H-indole: A Putative Aberrant Metabolite of 5-Hydroxytryptophan

Oxidative damage is known to occur in certain regions of the brain in a 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 of age-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 focused on 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 (LD50 = 3.3 μg) 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 it appears that 1 might be metabolized in vivo to metabolites that interact with certain 5-HT and perhaps other receptor subpopulations.