Synthesis, Biological Evaluation and Quantitative Structure Activity Relationship Analysis of Nuclear-substituted Pargylines as Competitive Inhibitors of MAO-A and MAO-B

Ali, Anmar; Robinson, J. B.

doi:10.1111/j.2042-7158.1991.tb03476.x

Cited by 14 publications

(8 citation statements)

References 22 publications

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“…The TEMPO-conjugated pargyline derivatives (ParSL-1, ParSL-2, and ParSL-3, Figure ) used in this work function as competitive MAOA and/or MAOB inhibitors, differing in their isoform specificities and kinetic properties. The inhibition process involves a reversible first step of enzyme−inhibitor complex formation, followed by the irreversible second step of covalent N(5) flavin adduct formation at the enzyme active sites . The kinetic parameters for the inhibition of MAOA and of MAOB activities by the flexible inhibitor ParSL-1 have been reported earlier and are reproduced in this work (Table ) as a comparison with those determined for the other two inhibitors (ParSL-2 and ParSL-3).…”

Section: Resultsmentioning

confidence: 66%

“…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.…”

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confidence: 99%

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

Upadhyay

Edmondson

2009

Biochemistry

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Three TEMPO conjugated pargyline analogues (ParSL-1, ParSL-2 and ParSL-3) have been synthesized and their inhibitory properties tested for the two human monoamine oxidase isoforms (hMAOA and hMAOB). The three analogues differ in flexibility and substituent positions (para or meta) of the linkers connecting the TEMPO group to the pargyline phenyl ring. ParSL-1 contains a flexible acetamido (-CH 2 -CO-NH-) linker connecting the two moieties at the para position. In contrast, the TEMPO moieties in ParSL-2 and ParSL-3 are attached with rigid amido (-CO-NH-) linkers to the para or meta positions of the pargyline phenyl ring, respectively. These variations in conformational flexibility and substituent position are shown to have profound effects in tuning the specificities of these analogues towards the two MAO isoforms. ParSL-1 irreversibly inhibits either MAOA and MAOB, ParSL-2 inhibits only MAOB (K i = 15 ± 5 μM), and ParSL-3 is found to be specific for MAOA (K i = 268 ± 72 μM). These results thus provide additional insights into the role of conformational flexibility and structural properties of MAO inhibitors in tuning their isoform specificities. These active site probes have been used to determine the topological orientation of these enzymes in the mitochondrial membrane. Studies with intact mitochondria show MAOA is topologically on the cytosolic face of the outer membrane in human placenta but recombinant MAOA is situated on the opposite inner face in Pichia mitochondria. Recombinant MAOB is found to be situated on the cytosolic face of the outer membrane in Pichia mitochondria.Of the spectroscopic probes available for membrane bound proteins, nitroxide spin labels are considered the most useful in defining structural properties of these important class of proteins. With advances in EPR and NMR methodologies, the design of enzyme-specific paramagnetic spin probes will allow understanding structural properties of these proteins in their native membrane-bound forms which can be extended to tissues samples as well as to subcellular organelles. Recent studies on human and rat monoamine oxidases (MAOA and MAOB) utilized a MAO -specific pargyline analogue containing a TEMPO spin label to show differences in active site accessibility (1) as well as demonstrated both isoforms are dimeric in their respective membrane bound forms in the outer mitochondrial membrane (OMM) (2). The crystal structures of hMAOA (3,4) and hMAOB (5) exhibit overall similarities in Cα-protein folds, as expected from their high sequence identities (ca. 70%). However, the structural properties of their active site cavities are quite different. The active site of hMAOB is dipartite with a substrate binding cavity (420 Å 3 ) and a substrate entrance cavity (290 Å 3 ) (5) separated by Ile199, whose side chain functions as a gate in regulating substrate/inhibitor binding (6). In contrast, the active site in hMAOA consists of a single substrate binding cavity (550 Å 3 ), which appears to provide more conformational flexibility for bound ligan...

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Section: Resultsmentioning

confidence: 66%

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confidence: 99%

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

Upadhyay

Edmondson

2009

Biochemistry

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“…However, for ethical and practical reasons, human tissues are difficult to obtain. In contrast, animal tissues, such as rat brain − or rat liver, , are easily accessible sources for in vitro screening of MAO B inhibitors, and therefore, rodents have been employed for most in vitro studies.…”

Section: Introductionmentioning

confidence: 99%

Impact of Species-Dependent Differences on Screening, Design, and Development of MAO B Inhibitors

et al. 2006

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The impact of species-dependent differences between human and rat MAO B on inhibitor screening was evidenced for two classes of compounds, coumarin and 5H-indeno[1,2-c]pyridazin-5-one derivatives. All examined compounds have shown a greater inhibitor potency toward human MAO B than toward rat MAO B. Moreover, no correlation was found between human and rat pIC(50) values. These divergences have important implications for the design and development of drugs involved in the MAO B metabolic pathway, suggesting that results obtained using rat enzyme cannot be extrapolated to human CNS, a priori. Indeed, the selection of a hit compound for lead generation could be different using human rather than rat enzyme. Moreover, the influence of substituents on the in vitro inhibition of human MAO B was markedly different between homogeneous series of coumarin and 5H-indeno[1,2-c]pyridazin-5-one derivatives, suggesting different binding modes, a hypothesis clearly supported by molecular docking simulations of inhibitors into the active site of human MAO B.

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“…Although attempts to formulate correlations that included both the meta-and para-substituted analogs failed, the authors were able to conclude that the binding site of MAO-B is likely to be present within a cavity of more limited lateral dimensions than that present on the MAO-A surface. 8 A novel opportunity to investigate the structuresubstrate activity relationships of molecules which contribute to MAO-A and MAO-B substrate selectivities has become available with the cyclic tertiary allylamine Some of the global structural features that are associated with MAO substrate properties of MPTP analogs include the following: (1) the six-membered heterocyclic system must contain the double bond at the position ß, to the nitrogen atom;11 (2) maximal activity requires an IV-methyl group;12 and (3) the 1-methyl-1,2,3 ,6-tetrahydropyridine ring must bear a C-4 substituent but no other ring carbon substituent. [13][14] In contrast to these restrictions, a wide variety of groups is tolerated at the C-4 position.…”

Section: Introductionmentioning

confidence: 99%

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

Wang¹,

Castagnoli²

1995

J. Med. Chem.

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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.

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Synthesis, Biological Evaluation and Quantitative Structure Activity Relationship Analysis of Nuclear-substituted Pargylines as Competitive Inhibitors of MAO-A and MAO-B

Cited by 14 publications

References 22 publications

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

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

Impact of Species-Dependent Differences on Screening, Design, and Development of MAO B Inhibitors

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

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