OXIDATION CHEMISTRY OF L-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 Disea se (AD) and transient cerebral ischemia and as a result of methampheta mine abuse. Furthermore, aberrant but unknown oxidized forms of 5-hydr oxytryptophan (5-HTPP) and 5-hydroxytryptamine (5-HT) have been detect ed in the cerebrospinal fluid (CSF) of AD patients but not in that of age-matched controls. Accordingly, it is possible that aberrant oxidat ive metabolites of 5-HTPP and 5-HT might play roles in the neurodegene rative processes that occur in the AD brain and other neurodegenerativ e 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 weak ly oxidizing conditions 1 is oxidized via a putative carbocation inter mediate 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 th e free hydroxyl residue of 1 to form a trimer, tetramer, and larger ol igomers that are subsequently further oxidized ultimately to dione 2. When administered into the brains of mice, 1 is a remarkably lethal co mpound (LD(50) = 3.3 mu g) and evokes a hyperactivity syndrome. Analys es of the brains of mice during this behavioral response reveal that a n acute dose of 1 evokes a significant decrease of norepinephrine (NE) levels. Only minor alterations in whole brain levels of DA and 5-HT o ccur but levels of 3,4-dihydroxyphenylacetic acid, homovanillic acid, and 5-hydroxyindole-3-acetic acid are significantly elevated. These re sults suggest that the hyperactivity syndrome evoked by 1 is related t o the elevated release and turnover of NE, DA, and 5-HT. Based upon th e results obtained and by comparison with other pharmacologic manipula tions that evoke a similar hyperactivity syndrome in mice and rats it appears that 1 might be metabolized in vivo to metabolites that intera ct with certain 5-HT and perhaps other receptor subpopulations. (C) 19 95 Academic Press, Inc.