Further Insights into the Oxidation Chemistry of Norepinephrine and Epinephrine in the Presence of Cysteine

Abstract

Oxidations of dopamine (DA), norepinephrine (NE), and epinephrine (EPI) at pH 7.4 in the presence of freeL-cysteine (CySH) have been previously shown to generate a number of cysteinyl conjugates of these catecholaminergic neurotransmitters that serve as precursors of various dihydrobenzothiazines (DHBTs). In this investigation it is demonstrated that oxidations of NE or EPI, but not DA, in the presence of free CySH also generate three previously unknown DHBTs: 6,8-bis[(2-amino-2-carboxyethyl)thio]-3,4-dihydro-5-hydroxy-2H-1,4-benzothiazine-3-carboxylic acid (A), 6,7,8-tris[(2-amino-2-carboxyethyl)thio]-3,4-dihydro-5-hydroxy-2H-1,4-benzothiazine-3-carboxylic acid (B), andN-[9-[(2-amino-2-carboxyethyl)thio]-7-carboxy-3,6,7,8-tetrahydro-10-hydroxybenzo[1,2-b: 4,3-b′]bis[1,4]thiazin-2-yl]-L-cystine (C). The β-hydroxy side chain residues of NE and EPI are required in order to formA–C,hence explaining the fact that these compounds are not formed upon oxidation of DA in the presence of CySH. A further new product unique to the oxidation of EPI in the presence of CySH at pH 7.4 isN-[6-[(2-amino-2-carboxyethyl)thio]-2,7-dihydro-5-hydroxy-7-methylpyrrolo[2,3-h]-1,4-benzothiazin-3-yl]-L-cystine (D). Reactions pathways that account for formation ofA–Dare presented along with a discussion of their potential formation as aberrant metabolites in the brain in a number of neurodegenerative disorders.