Bioactivation of Cathaedulis alkaloids: Enzymatic ketonization of norpseudoephedrine

Abstract Among the phenylalkylamines which have been shown to have potent central nervous system stimulatory activity are (+)-norpseudoephedrine and its ketone analog, cathinone, and recent work has suggested that cathinone is the more potent agent of the two. We have found that (+)-norpseudoephedrine is oxygenated by dopamine-β-hydroxylase, producing cathinone with the expected stoichiometry of electrons to O 2 to product of 2:1:1 diagnostic of a monooxygenase-catalyzed reaction. A k cat value of 10 sec −1 and K m of 18.8 m M were obtained, indicating that this reaction proceeds readily enough to be of physiological significance. The delayed onset and long duration of action of (+)-norpseudoephedrine is consistent with a requirement for enzyme activation and thus it is possible that dopamine-β-hydroxylase-catalyzed ketonization mediates the potent stimulatory effect of this and related compounds.