REACTIONS OF CYSTEINE AND CYSTEINYL DERIVATIVES WITH DOPAMINE-O-QUINONE AND FURTHER INSIGHTS INTO THE OXIDATION CHEMISTRY OF 5-S-CYSTEINYLDOPAMINE - POTENTIAL RELEVANCE TO IDIOPATHIC PARKINSONS-DISEASE

Recent studies suggest that elevated rates of autoxidation of dopamine (DA) in the cytoplasm of neuromelanin-pigmented dopaminergic cell bod ies in the substantia nigra (SN) and/or reactions of its proximate oxi dation product, DA-o-quinone, with glutathione (GSH) or L-cysteine (Cy SH) might yield endotoxins that play roles in the pathogenesis of idio pathic Parkinson's Disease (PD). In this study the reactions between D A-o-quinone and CySH and some cysteine derivatives have been studied. The reactions between DA-o-quinone and CySH or cysteine methyl ester a re rapid and give the corresponding 5-S-cysteinyl conjugates of DA as the predominant products. By contrast, the reaction between the steric ally hindered D-penicillamine methyl ester (PME) and DA-o-quinone is m uch slower to give, initially, a mixture of the 2-S-, 5-S-, and 6-S-PM E conjugates of DA. These conjugates are then further oxidized by unre acted DA-o-quinone to give a complex mixture of products which include ydroxy-2,2-dimethyl-1,4-benzothiazine-3-carboxylic acid methyl ester (13). Large increases in the 5-S-cysteinyldopamine (5-S-CyS-DA)/DA con centration ratio have been measured in the Parkinsonian SN and have be en interpreted to reflect elevated rates of DA autoxidation in this st ructure that degenerates in PD. However, the present study reveals tha t at physiological pH 5-S-CyS-DA is not only more easily oxidized than DA but a bicyclic o-quinone imine (5) intermediate is formed that can chemically oxidize the former conjugate in a reaction that leads to i hydro-5-hydroxy-2H-1,4-benzothiazine-3-carboxylic acid (6). Compound 6 is lethal when administered into the brains of mice. However, this pu tative dihydrobenzothiazine endotoxin is even more easily oxidized tha n 5-S-CyS-DA in a rather complex reaction that ultimately forms inoeth yl)-5-hydroxy-1,4-benzothiazine-3-carboxylic acid (15). Although this benzothiazine could not be isolated it was identified by comparison of its electrochemical and spectroscopic properties in solution with tho se of 13. The results of this study suggest that benzothiazine 15 migh t serve as a better analytical marker molecule than 5-S-CyS-DA for eit her elevated rates of DA autoxidation and/or for roles of GSH and CySH in the neurodegenerative mechanisms in the SN that contribute to PD. (C) 1995 Academic Press, Inc.