RT Journal Article
SR Electronic
T1 Application of chemical cytochrome P-450 model systems to studies on drug metabolism. IV. Mechanism of piperidine metabolism pathways via an iminium intermediate.
JF Drug Metabolism and Disposition
JO Drug Metab Dispos
FD American Society for Pharmacology and Experimental Therapeutics
SP 768
OP 780
VO 19
IS 4
A1 H Masumoto
A1 S Ohta
A1 M Hirobe
YR 1991
UL http://dmd.aspetjournals.org/content/19/4/768.abstract
AB Oxidations of the piperidine ring by chemical model and liver microsomal systems were investigated with a simple piperidine derivative, N-benzylpiperidine (BP) (3), as the substrate in order to probe the generality and the mechanism of the biotransformation of the piperidine ring. The piperidine ring of BP (3) as well as that of phencyclidine (1) was suggested to be oxidized to a ketone at the beta-position in the meso-tetraphenylporphinatoiron(III) chloride system, and the reaction was expected to occur in the liver microsomal system. The beta-oxo formation was observed directly in the liver microsomal system, and found to be dependent on cytochrome P-450. Then it was suggested that the piperidine-beta-oxo formation was a general oxidation pathway of the piperidine biotransformation. Hydrogen abstraction in the reaction was not a rate-determining step. Therefore, we presumed a possible mechanism of beta-oxo formation via BP-iminium (21). From the comparative study on the reactivities of dipropylbenzylamine (DPB) (18) and BP (3), and the stabilities of iminium (Im+) species of BP (3) and DPB (18), it was suggested that BP-Im+ (21) was relatively stable and was the most likely precursor of BP-beta-oxo (6). BP-Im+ (21) and its free base, enamine (29), afforded large amounts of BP-beta-oxo as well as BP-alpha-oxo (9) in the chemical model and the microsomal systems. This evidence supported the iminium-enamine mechanism expressed as scheme III.