The aim of this project is to employ electrochemical and other analytical techniques to investigate the oxidation chemistry of naturally occurring or otherwise biologically significant indoles. These will include the 5-hydrosylated metabolites of tryptophan, N-methylated indoles (such as bufotenin) which are implicated in the etiology of schizophrenia and depression, and 5,6- and 5,7-dihydrosytryptamines (5,6- and 5,7-DHT) which are powerful neurotoxins. Anomalous, minor oxidation pathways of, for example, the enurotransmitter 5-hydrosytryptamine have been speculated to play a role in some mental disorders. Similarly, the neurotoxicity of 5,6- and 5,7DHT is thought to be due to reactions of their reactive autoxidation products in the CNA. Many of these indoles undergo oxidation reactions in biological systems yet virtually nothing is known about the mechanisms and products of these processes. Modern electroanalytical techniques will be used to elucidate the nature of the primary oxidation step and the identity and properties of transient intermediates. Longer lived intermediates will be further studied using spectral and chromatographic methods, particularly GC-MS and LC-MS techniques. Reaction products will be isolated and identified using a wide range of analytical techniques including column chromatography, HPLC, U.V.-vis, I.R., NMR and mass spectrometry. Evidence concerning the biological relevance of such studies will be obtained by investigating the oxidation of these indoles with various CNS enzymes and critically comparing the courses of the electrochemical and enzymatic oxidations. In vivo evaluations of the neurotoxic properties of the many new products formed by electrochemical and enzymatic oxidation are planned. Electrochemical and other analytical techniques will be used to study the interactions of the very reactive primary oxidation products of indoles (quinones, quinoneimines, methyleneimines) with nucleophiles commonly found in CNS tissue (thiols, amino acids, water). The long range goal is to develop a fundamental understanding of the oxidation chemistry of biologically significant indoles. This, in turn, could provide a basis for understanding the oxidation chemistry of such indoles in living systems which might give important insights into a chemical basis for some mental illnesses and other disease states.
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