80353-09-9Relevant academic research and scientific papers
Synthesis and monoamine oxidase B catalyzed oxidation of C-4 heteroaromatic substituted 1,2,3,6-tetrahydropyridine derivatives
Nimkar, Sandeep K.,Anderson, Andrea H.,Rimoldi, John M.,Stanton, Matthew,Castagnoli, Kay P.,Mabic, Stephane,Wang,Castagnoli Jr., Neal
, p. 1013 - 1022 (2007/10/03)
The monoamine oxidase B (MAO-B) catalyzed oxidation of amines has been proposed to proceed via a polar pathway, an initial single-electron transfer pathway and an initial hydrogen atom transfer pathway. Results from previous studies on selected N-cyclopropyl-4-substituted-1,2,3,6-tetrahydropyridine derivatives have led us to consider a mechanism for these cyclic tertiary allylamines which may not necessarily involve the aminyl radical cation as required by an initial single-electron transfer step. The studies summarized in this paper were undertaken to explore further the structural features that determine the MAO-B substrate and/or inactivator properties of various 1,4-disubstituted tetrahydropyridine 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 heteroaromatic groups at C-4. All of the N-cyclopropyltetrahydropyridine analogs were time and concentration dependent inhibitors of MAO-B while all of the N-methyltetrahydropyridine analogs and the N-cyclopropyl-4-(1- methyl-2-pyrryl)tetrahydropyridine analog were substrates. The substrate properties (k(cat)/K(M)) covered a range of 6 to 1800 min-1 mM-1 while the range for the inactivator properties for which k(inact)/K(I) values 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 results are discussed in terms of the putative allylic radical intermediate and in the context of the hydrogen atom transfer and single-electron transfer based mechanisms.
Molecular Size and Flexibility as Determinants of Selectivity in the Oxidation of N-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine Analogs by Monoamine Oxidase A and B
Efange, S. M. N.,Michelson, R. H.,Tan, A. K.,Krueger, M. J.,Singer, T. P.
, p. 1278 - 1283 (2007/10/02)
The introduction of a methylene bridge between the phenyl and tetrahydropyridyl moieties of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) results in increased selectivity for monoamine oxidase B (MAO B) over monoamine oxidase A (MAO A). However, lengthening of this bridge results in a total loss of selectivity. In the present study, a number of isomeric 4-naphthyl-, 4-(naphthylalkyl)-, 4-thienyl-, and 4-(thienylalkyl)tetrahydropyridines, conformationally restrained and flexible analogs of MPTP, were synthesized and evaluated as potential selective substrates of MAO A and B. In terms of the parameter (turnover number)/Km, the bulky naphthyl analogs were invariably better substrates of MAO A than kynuramine, the reference substrate for this enzyme. In addition, all naphthyl analogs, regardless of conformational mobility, were more effective substrates of MAO A than MAO B. Similarly, all thienyl analogs were found to be more effective substrates of MAO B. In contrast to the naphthalenes, the conformationally restrained thiophenes 9a and 10a were found to be poor substrates of MAO B, relative to benzylamine, the reference substrate. These results suggest that the selectivity of these compounds for either MAO A or B is determined by the complex interplay of molecular size and flexibility. In this interplay, either one of these two factors may predominate.
