Regioselective O-methylation of tetrahydropapaveroline and tetrahydroxyberbine in vivo in rat brain.
Enzymatic O-methylation is a primary pathway for the metabolism of catecholamines in mammals and of isoquinoline alkaloids in plants. This report describes the differential O-methylation patterns of the racemates and enantiomers of two catecholamine-derived alkaloids, tetrahydropapaveroline (THP) and 2,3,10,11-tetrahydroxyberbine (THB), in the brain of the rat. One hour after intracerebroventricular administration of a specific isomeric form of each alkaloid, the O-methylated metabolites were isolated from the rat brain and subsequently quantified using high performance liquid chromatography. The isomeric form of THP or THB which was administered markedly influenced the pattern of O-methylation. The racemate and R-(+)-enantiomer of THP were mono-O-methylated predominantly at the 7 and 3' positions, while the S-(-)-enantiomer of THP was mono-O-methylated to an essentially equal degree at the 6, 7 and 3' positions. Minimal mono-O-methylation at the 4' position was detectable only with the racemate and (-)-enantiomer of THP. The racemate and enantiomers of THB were mono-O-methylated predominantly at the 2 and 11 positions and to a lesser extent at the 3 and 10 positions. Although minimal with the R-(+)-enantiomer, the 3 and the 10-O-methylation pathways were enhanced significantly with the S-(-)-enantiomer of THB. These results demonstrate that both enantiomers of THP and THB are O-methylated in vivo in rat brain and that the chiral centers of these alkaloids influence the position of O-methylation, thereby dictating the relative amounts of specific products formed.
D000818:Animals; D001600:Berberine Alkaloids / Q000378:metabolism*; D001921:Brain / Q000378:metabolism*; D002851:Chromatography, High Pressure Liquid; D008297:Male; D008745:Methylation; D008780:Methyltransferases / Q000378:metabolism*; D010208:Papaverine / Q000031:analogs & derivatives*; D051381:Rats; D011919:Rats, Inbred Strains; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D013765:Tetrahydropapaveroline / Q000378:metabolism*
D001600:Berberine Alkaloids; D013765:Tetrahydropapaveroline; C039488:2,3,10,11-tetrahydroxyberbine; D010208:Papaverine; D008780:Methyltransferases