Rat liver microsomal enzyme catalyzed oxidation of 4-phenyl-trans-1-(2-phenylcyclopropyl)-1,2,3,6-tetrahydropyridine

As part of our ongoing studies to characterize the catalytic pathway(s) for the monoamine oxidase and cytochrome P450 catalyzed oxidations of 1,4-disu bstituted 1,2,3,6-tetrahydropyridinyl derivatives, we have examined the met abolic fate of e-phenyl-trans- 1-(2-phenylcyclopropyl)-1,2,3,6-tetrahydropy ridine in NADPH supplemented rat liver microsomes. Three metabolic pathways have been identified: (1) allylic ring alpha -carbon oxidation to yield th e dihydropyridinium species. (2) nitrogen oxidation to yield the N-oxide an d (3) N-dealkylation to yield 4-phenyl-1,2,3,6-tetrahydropyridine and cinna maldehyde. A possible mechanism to account for the formation of cinnamaldeh ye involves an initial single electron transfer from the nitrogen lone pair to the iron oxo system Fe+3(O) to form the corresponding cyclopropylaminyl radical cation that will be processed further to the final products. The r eaction pathway leading to the dihydropyridinium metabolite may also procee d via the same radical cation intermediate but direct experimental evidence to this effect remains to be obtained. (C) 2001 Elsevier Science Ltd. All rights reserved.