INFLUENCE OF L-CYSTEINE ON THE OXIDATION CHEMISTRY OF (-)-EPINEPHRINE- FORMATION OF CYSTEINYL CONJUGATES AND NOVEL DIHYDROBENZOTHIAZINES

Oxidation of epinephrine (EPI) in aqueous solution at pH 7.4 generates an ortho-quinone (1) that normally deprotonates and undergoes a rapid intramolecular cyclization and secondary reactions, ultimately leadin g to an indolic melanin polymer. In this investigation, it is demonstr ated that L-cysteine (CySH) can intervene in this reaction by scavengi ng o-quinone 1 to give 5-S-cysteinylepinephrine (5-S-CyS-EPI) and 2-S- cysteinylepinephrine (2-S-CyS-EPI). Subsequent oxidation (2e, 2H(+)) o f the latter cysteinyl conjugates gives o-quinones that can either rea ct further with free CySH to give the 2,5-bi-S- and 2,5,6-tri-S-cystei nyl conjugates of EPI or cyclize to give ihydro-5-hydroxy-2H-1,4-benzo thiazine-3-carboxylic acid (DHBT-E1) and ihydro-5-hydroxy-2H-1,4-benzo thiazine-3-carboxylic acid (DHBT-E2), respectively. Oxidations of 2,5- bi-S-CyS-EPI and 2,5,6-tris-S-CyS-EPI and of DHBT-E1 and DHBT-E2 in th e presence of CySH provide routes to a number of other dihydrobenzothi azines (DHBTs). Four new cysteinyl conjugates of EPI and seven DHBTs h ave been isolated and their structures elucidated by spectroscopic met hods. Based upon a number of lines of converging evidence, it is sugge sted that these compounds might include unusual metabolites of EPI for med in adrenergic neurons under certain pathological brain conditions. (C) 1996 Academic Press, Inc.