Studies on the Monoamine Oxidase (MAO)-Catalyzed Oxidation of Phenyl-Substituted 1-Methyl-4-phenoxy-1,2,3,6-tetrahydropyridine Derivatives: Factors Contributing to MAO-A and MAO-B Selectivity

Abstract

The structural parameters responsible for the substrate and inhibitor selectivities of the monoamine oxidases (MAO) A and B remain poorly understood. This situation has improved somewhat with structure-activity studies that have been performed on nuclear-substituted pargyline derivatives and 4-substituted 1-methyl-1,2,3,6-tetrahydropyridine derivatives. The results of these studies suggest that the active site of MAO-A is sterically more accommodating than the active site of MAO-B. In the present work we have undertaken a more systematic structure-substrate activity analysis with the aid of a series of 4-phenoxytetrahydropyridine analogs substituted at the para, meta, and ortho positions of the phenyl ring with chloro, methoxy, methyl, nitro, and phenyl groups. All of the compounds proved to be good substrates for both MAO-A and MAO-B, and all were better MAO-A substrates than MAO-B substrates. The best defined structural parameter relating to selectivity again was the relatively better MAO-A substrate properties of tetrahydropyridine derivatives bearing bulky C-4 substituents. Attempts to identify stereoelectronic effects related to substrate properties and selectivity with this series of compounds were not successful. Although some structural correlates with substrate activity can be made, overall the present state of knowledge is inadequate to provide good descriptors of structural features that characterize MAO-A and MAO-B substrates.

Assessment of Structural Requirements for the Monoamine Oxidase-B-Catalyzed Oxidation of 1,4-Disubstituted-1,2,3,6-tetrahydropyridine Derivatives Related to the Neurotoxin 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine

“…Consequently, the poor substrate properties of the 4-p-hydroxy, -amino, and -nitro derivatives 8, 17, and 18, respectively, and the 4-carbamoyloxy derivatives 35 and 36 may partially be explained in terms of unfavored polar interactions within the active site. Nevertheless, other polar derivatives (e.g., the (nitrophenoxy)-1-methyl-1,2,3,6-tetrahydropyridine derivatives) 6 show good to excellent MAO-B substrate properties suggesting that favorable electrostatic interactions also may play a role.…”

“…Both flexible (one or more sp 3 -hybridized atoms) and constrained (aryl) C 4 substituents may be well tolerated by both MAO-A and MAO-B, 5 although the MAO-A active site appears to accommodate bulkier groups at C 4 better than does the active site of MAO-B. 3,6 Only substitutions at the N 1 and C 4 positions of the THP ring are tolerated, 7 and apparently, only small substituents can be accommodated at the N 1 position. On the basis of results with a limited set of compounds, Efange suggested a maximum distance of 10.23 Å between the N-methyl carbon and the farthest carbon on the C 4 substituent.…”

Development of Spin-Labeled Pargyline Analogues as Specific Inhibitors of Human Monoamine Oxidases A and B

“…Such studies have been reported on human MAOA, bovine MAOB, and on the two rat MAOs; using various modified inhibitors (pargyline, clorgyline) and substrate (benzylamine) analogues (7-13). The SAR studies using a series of ring substituted pargyline analogues on rat MAOA and MAOB (rMAOA and rMAOB) have shown that the position of substitution on the aromatic ring of pargyline ( meta vs. para ) influences the isoform specificities of the corresponding inhibitor analogues.…”

Light-Up Probes Based on Fluorogens with Aggregation-Induced Emission Characteristics for Monoamine Oxidase-A Activity Study in Solution and in Living Cells

“…As shown in Scheme A, the TPE based MAO probe is composed of an N -methyl phenylpyridium, a TPE fluorogen, and a C–C double bond linker. The N -methyl phenylpyridium and its analogues are unique inhibitors with high binding affinity toward both MAO-A and MAO-B. − TPE, as a large substituent at 4-position of phenylpyridium, is expected to make the probe more selective toward MAO-A . The positively charged pyridium moiety is hydrophilic, which should render the probe dispersible in aqueous media, especially at low concentrations.…”