Non-enzymatic Oxidation of the New Cardiotonic Agent Denopamine and Its Derivatives : Comparison with Enzymatic Oxidation

Chemical oxidation of the positive inotropic agent denopamine, (-)-(R)-1-(p-hydroxyphenyl)-2-[(3, 4-dimethoxyphenethyl) amino] ethanol, and its derivatives by Udenfriend's model system for enzymatic oxidation was studied. The oxidation products were separated and identified by gas chromatography-mass spectrometry and high-performance liquid chromatography. All the metabolites of denopamine produced by enzymatic oxidation were also formed in Udenfriend's system. However, compared to enzymatic oxidation, the chemical oxidation was less selective as to the position of demethylation : i.e., although enzymatic 4'-O-demethylation took place overwhelmingly in preference to 3'-O-demethylation, comparable amounts of the two demethylated isomers were produced in Udenfriend's system. It was also found that the chemical oxidation was more powerful than the enzymatic oxidation because hydroxylation at the ortho or para position to the methoxy group took place in all the substrates tested, while such metabolites have not been detected in biological systems. As in the enzymatic system, tetrahydroisoquinoline-type compounds were formed from substrates in which the hydroxy group was attached at the meta position of the benzene ring. This is presumably a result of Pictet-Spengler-type condensation with formaldehyde generated in the reaction mixture.