Oxidation chemistry of (-)-norepinephrine in the presence of L-cysteine.
The noradrenergic neurotransmitter (-)-norepinephrine (1) is very easily oxidized at physiological pH to an o-quinone (2) that normally cyclizes and subsequently oxidatively polymerizes to black melanin. In this investigation it is demonstrated that L-cysteine (CySH) can divert the melanin pathway by efficiently scavenging o-quinone 2 to give, initially, 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 give 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 derived in a reaction sequence that leads initially to a number of dihydrobenzothiazines. At least two of these compounds, 7-(1-hydroxy-2-aminoethyl)-3,4-dihydro-5- hydroxy-2H-1,4-benzothiazine-3-carboxylic acid (9) and 8-(1-hydroxy-2-aminoethyl)-3,4-dihydro-5-hydroxy-2H-1, 4-benzothiazine-3-carboxylic acid (10) are lethal when administered into the brains of mice. The in vitro chemical pathways elucidated in this investigation might be of relevance to the depigmentation and degeneration of neuromelanin-pigmented noradrenergic cell bodies in the locus ceruleus in Parkinson's Disease and to the degeneration of noradrenergic nerve terminals in Alzheimer's Disease and following transient cerebral ischemia (stroke).
Shen
X M
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Department of Chemistry and Biochemistry, University of Oklahoma, Norman 73019, USA.
Dryhurst
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D000818:Animals; D003545:Cysteine / Q000737:chemistry*; D004563:Electrochemistry; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D009638:Norepinephrine / Q000737:chemistry*; D010084:Oxidation-Reduction; D016339:Spectrometry, Mass, Fast Atom Bombardment; D013843:Thiazines / Q000737:chemistry / Q000633:toxicity
D013843:Thiazines; D003545:Cysteine; D009638:Norepinephrine