SYNTHESIS AND MONOAMINE-OXIDASE-B CATALYZED OXIDATION OF C-4 HETEROAROMATIC SUBSTITUTED 1,2,3,6-TETRAHYDROPYRIDINE DERIVATIVES

The monoamine oxidase B (MAO-B) catalyzed oxidation of amines has been proposed to proceed via a polar pathway, an initial single-electron t ransfer pathway and an initial hydrogen atom transfer pathway. Results from previous studies on selected clopropyl-4-substituted-1,2,3,6-tet rahydropyridine derivatives have led us to consider a mechanism for th ese cyclic tertiary allylamines which may not necessarily involve the aminyl radical cation as required by an initial single-electron transf er step. The studies summarized in this paper were undertaken to explo re further the structural features that determine the MAO-B substrate and/or inactivator properties of various 1,4-disubstituted tetrahydrop yridine derivatives. We report here the results of our studies on the synthesis and MAO-B catalyzed oxidation of 1-methyl- and 1-cyclopropyl -1,2,3,6-tetrahydropyridine derivatives bearing a variety of heteroaro matic groups at C-4. All of the N-cyclopropyltetrahydropyridine analog s were time and concentration dependent inhibitors of MAO-B while all of the N-methyltetrahydropyridine analogs and the yclopropyl-4-(1-meth yl-2-pyrryl)tetrahydropyridine analog were substrates. The substrate p roperties (k(cat)/K-M) covered a range of 6 to 1800 min(-1) mM(-1) whi le the range for the inactivator properties for which k(inact)/K-I val ues could be obtained was 0.1-1.0 min(-1) mM(-1). The partition ratios for the N-cyclopropyl analogs varied from 4 to 17 except for the 4-(1 -methyl-2-pyrryl) analog, which had a partition ratio of 400. These re sults are discussed in terms of the putative allylic radical intermedi ate and in the context of the hydrogen atom transfer and single-electr on transfer based mechanisms.