OXIDATION CHEMISTRY OF (-)-NOREPINEPHRINE IN THE PRESENCE OF L-CYSTEINE

The noradrenergic neurotransmitter (-)-norepinephrine (1) is very easi ly oxidized at physiological pH to an o-quinone (2) that normally cycl izes and subsequently oxidatively polymerizes to black melanin. In thi s investigation it is demonstrated that L-cysteine (CySH) can divert t he melanin pathway by efficiently scavenging o-quinone 2 to give, init ially, 5-S-cysteinylnorepinephrine (6) and 2-S-cysteinylnorepinephrine (7). These cysteinyl conjugates are appreciably more easily oxidized than 1 to o-quinones that, in part, are further attacked by CySH to gi ve 2,5-bi-S-cysteinylnorepinephrine (8), an even more easily oxidized compound. The o-quinone intermediates formed upon oxidation of 6-8 can also undergo facile intramolecular cyclizations to bicyclic o-quinone imines that oxidize the cysteinyl conjugates from which they are deri ved in a reaction sequence that leads initially to a number of dihydro benzothiazines. At least two of these compounds, ihydro-5-hydroxy-2H-1 ,4-benzothiazine-3-carboxylic acid (9) and ihydro-5-hydroxy-2H-1,4-ben zothiazine-3-carboxylic acid (10) are lethal when administered into th e brains of mice. The in vitro chemical pathways elucidated in this in vestigation might be of relevance to the depigmentation and degenerati on of neuromelanin-pigmented noradrenergic cell bodies in the locus ce ruleus in Parkinson's Disease and to the degeneration of noradrenergic nerve terminals in Alzheimer's Disease and following transient cerebr al ischemia (stroke).