STEREOSELECTIVE ENZYMATIC O-METHYLATION OF TETRAHYDROPAPAVEROLINE AND TETRAHYDROXYBERBINE ALKALOIDS

Modification of neuroamine metabolism leading to the formation of isoquinoline alkaloids has been the target of several investigations. This study describes the differential enzymatic O-methylation pattern of the racemates and optical isomers of tetrahydropapaveroline (THP) and 2,3,10,11-tetrahydroxy-berbine (THB) by a rat liver catechol O-methyltransferase (COMT) preparation. Reaction products were separated and isolated by high-pressure liquid chromatography, and structural identity was confirmed by synthesis and gas chromatography/mass spectrometry. The positions of enzymatic O-methylations were markedly influenced by the particular optical isomeric form of substrate employed. The optical isomers and racemates of THP and THB were mainly mono-O-methylated with trace amounts of di-O-methylation. The mono-O-methylations of THP were contained exclusively in the isoquinoline ring at positions 6 or 7, while mono-O-methylations of THB occurred at the vicinal hydroxyl groups of both rings A and D. This enzymatic process was evaluated further by examining the effect of classical inhibitors of COMT on these O-methylations. The results presented demonstrate that vicinal hydroxyl moieties of THP and THB are mono-O-methylated at either of the sites and that the magnitude of the positional isomer product ratio results from the optical isomeric orientation in which the substrate binds to the enzyme. © 1979.