6-Hydroxydopamine (6-OHDA), 5,6-dihydroxytryptamine (5,6-DHT) and 5,7-dihydroxytryptamine (5,7-DHT) are important pharmacological tools used to produce chemical denervation of noradrenergic, dopaminergic and serotonergic neurons. The primary objectives of this program are to elucidate the molecular mechanisms through which these agents produce their neurotoxicity and to use this information to rationally design new, more selective neurotoxins for monoaminergic neurons. These objectives are being accomplished through the design, synthesis and biological evaluation of analogs of 6-OHDA, 5,6-DHT and 5,7-DHT. These analogs are being designed to have predictable redox potentials and predictable reactivities with protein nucleophiles. The new analogs to be synthesized during this renewal period include 2- and/or 5-fluorinated analogs of 6-OHDOPA, 2- and/or 5-fluorinated analogs of 6-OHNE, 2- and/or 5- fluorinated analogs of 6-OHEpi, and 4- and/or 6-fluorinated analogs of 5,7-DHT. The following studies will be carried out using the fluorinated analogs of 5,7-DHT, 6-OHDOPA, 6-OHNE, 6-OHEpi, 5,6-DHT and 6-OHDA: (1) determination of redox potentials; (2) polarographic measurement of the spontaneous- and mitochondria-promoted oxidation; (3) reactivity with glutathione; (4) spectroscopic studies (UV, NMR, EPR) to determine the structure and reactivity of initial air oxidation products; (5) neurotoxicity after intraventricular injection in rats; (6) neurotoxicity to neuroblastoma cells in culture; (7) affinities for the monoaminergic uptake systems; and (8) the relationship between protein binding and cytotoxicity. In addition, C-methylated analogs of 6-OHDA and 5,6-DHT will be labeled with [H3] at positions thought to be reactive with protein nucleophiles and with [C14] at a chemically and metabolically stable position as a reference marker. These [H3], [C14]-labeled analogs will be used to characterize the structures of the adduct formed when these neurotoxins react with endogenous protein nucleophiles in neuroblastoma cells in culture. The results of these studies should improve our understanding of the molecular mechanisms by which these agents produce neurotoxicity and, thereby, permit the rational design of more specific target-directed neurocytotoxins which can be used to elucidate the intricacies of the central nervous system.
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