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Jacobus P. Petzer - One of the best experts on this subject based on the ideXlab platform.

  • Monoamine Oxidase Inhibition by Kavalactones from Kava (Piper Methysticum)
    Planta Medica, 2019
    Co-Authors: Denise Prinsloo, Anél Petzer, Jacobus P. Petzer
    Abstract:

    Monoamine Oxidases (MAOs) are key metabolic enzymes for neurotransmitter and dietary amines and are targets for the treatment of neuropsychiatric and neurodegenerative disorders. This study examined the MAO Inhibition potential of kavain and other kavalactones from the roots of kava (Piper methysticum), a plant that has been used for its anxiolytic properties. (±)-Kavain was found to be a good potency in vitro inhibitor of human MAO-B with an IC50 of 5.34 µM. (±)-Kavain is a weaker MAO-A inhibitor with an IC50 of 19.0 µM. Under the same experimental conditions, the reference MAO inhibitor, curcumin, displays IC50 values of 5.01 µM and 2.55 µM for the Inhibition of MAO-A and MAO-B, respectively. It was further established that (±)-kavain interacts reversibly and competitively with MAO-A and MAO-B with enzyme-inhibitor dissociation constants (Ki) of 7.72 and 5.10 µM, respectively. Curcumin in turn, displays a Ki value of 3.08 µM for the Inhibition of MAO-A. Based on these findings, other kavalactones (dihydrokavain, methysticin, dihydromethysticin, yangonin, and desmethoxyyangonin) were also evaluated as MAO inhibitors in this study. Yangonin proved to be the most potent MAO inhibitor with IC50 values of 1.29 and 0.085 µM for MAO-A and MAO-B, respectively. It may be concluded that some of the central effects (e.g., anxiolytic) of kava may be mediated by MAO Inhibition.

  • Methylene Blue Analogues with Marginal Monoamine Oxidase Inhibition Retain Antidepressant-like Activity
    2018
    Co-Authors: Anzelle Delport, Anél Petzer, Brian H. Harvey, Jacobus P. Petzer
    Abstract:

    Methylene blue (MB) possesses diverse medical applications. Among these, MB presents with antidepressant-like effects in animals and has shown promise in clinical trials for the treatment of mood disorders. As an antidepressant, MB may act via various mechanisms which include modulation of the nitric oxide cyclic guanosine monophosphate (NO-cGMP) cascade, enhancement of mitochondrial respiration and antioxidant effects. MB is also, however, a high potency inhibitor of Monoamine Oxidase (MAO) A, which most likely contributes to its antidepressant effect, but also to its adverse effects profile (e.g., serotonin toxicity). The latter has raised the question whether it is possible to design out the MAO Inhibition properties of MB yet retaining its clinically useful attributes. This study explores this idea further by characterizing five newly synthesized low MAO-A active MB analogues and examining their antidepressant-like properties in the acute forced swim test (FST) in rats, with comparison to imipramine and MB. The results show that all five analogues exhibit antidepressant-like properties in the FST without confounding effects on locomotor activity. The magnitude of these effects is comparable to those of imipramine and MB. Moreover, these newly synthesized MB analogues are markedly less potent MAO-A inhibitors (IC50 = 0.518–4.73 μM) than MB (IC50 = 0.07 μM). We postulate that such lower potency MAO-A inhibitors may present with a reduced risk of adverse effects associated with MAO-A Inhibition. While low level MAO-A Inhibition still may produce an antidepressant effect, we posit that other MB-related mechanisms may underlie their antidepressant effects, thereby representing a novel group of antidepressant compounds

  • The Monoamine Oxidase Inhibition properties of selected structural analogues of methylene blue.
    Toxicology and applied pharmacology, 2017
    Co-Authors: Anzelle Delport, Anél Petzer, Brian H. Harvey, Jacobus P. Petzer
    Abstract:

    The thionine dye, methylene blue (MB), is a potent inhibitor of Monoamine Oxidase (MAO) A, a property that may, at least in part, mediate its antidepressant effects in humans and animals. The central Inhibition of MAO-A by MB has also been linked to serotonin toxicity (ST) which may arise when MB is used in combination with serotonergic drugs. Structural analogues and the principal metabolite of MB, azure B, have also been reported to inhibit the MAO enzymes, with all compounds exhibiting specificity for the MAO-A isoform. To expand on the structure-activity relationships (SARs) of MAO Inhibition by MB analogues, the present study investigates the human MAO Inhibition properties of five MB analogues: neutral red, Nile blue, new methylene blue, cresyl violet and 1,9-dimethyl methylene blue. Similar to MB, these analogues also are specific MAO-A inhibitors with cresyl violet (IC50=0.0037μM), Nile blue (IC50=0.0077μM) and 1,9-dimethyl methylene blue (IC50=0.018μM) exhibiting higher potency Inhibition compared to MB (IC50=0.07μM). Nile blue also represents a potent MAO-B inhibitor with an IC50 value of 0.012μM. From the results it may be concluded that non-thionine MB analogues (e.g. cresyl violet and Nile blue) also may exhibit potent MAO Inhibition, a property which should be considered when using these compounds in pharmacological studies. Benzophenoxazines such as cresyl violet and Nile blue are, similar to phenothiazines (e.g. MB), representative of high potency MAO-A inhibitors with a potential risk of ST.

  • Monoamine Oxidase Inhibition by C4-substituted phthalonitriles
    Bioorganic chemistry, 2011
    Co-Authors: Clarina I. Manley-king, Jacobus J. Bergh, Jacobus P. Petzer
    Abstract:

    Abstract It was recently reported that a series of C5-substituted phthalimides are remarkably potent reversible inhibitors of recombinant human Monoamine Oxidase (MAO) B. Modeling studies suggested that the phthalimide ring forms numerous polar interactions with the polar region of the MAO-B substrate cavity while the C5 side chain extends to, and interacts via Van der Waals interactions with the hydrophobic regions of the enzyme entrance cavity. Interactions with both cavities appear to be requirements for high affinity binding. In the present study we have examined an analogs series of C4-substituted phthalonitriles as potential human MAO inhibitors. The phthalonitriles were found to be highly potent reversible MAO-B inhibitors with most analogs exhibiting IC 50 values in the low nM range. The phthalonitriles also interacted with human MAO-A, although with lower binding affinities compared to MAO-B. Modeling studies suggest that the high binding affinities of the phthalonitriles to MAO-B may depend, at least in part, on the formation of polar interactions between the nitrile functional groups and the enzyme substrate cavity. Examination of a homologs series of benzonitriles established that the phthalonitrile moiety is more optimal for MAO-B Inhibition than the corresponding benzonitrile moiety, and that C3-substituted benzonitriles are better MAO-B inhibitors than C4-substituted benzonitriles. Since elimination of the nitrile functional group yielded compounds with only moderate MAO-B Inhibition potencies, it may be concluded that this functional group is privileged for MAO-B Inhibition.

  • Monoamine Oxidase Inhibition by selected anilide derivatives
    European journal of medicinal chemistry, 2011
    Co-Authors: Lesetja J. Legoabe, Anél Petzer, Jacobus J. Bergh, Johann Kruger, Jacobus P. Petzer
    Abstract:

    Abstract A series of anilide derivatives were synthesized and evaluated as inhibitors of recombinant human Monoamine Oxidase (MAO) A and B. The most potent inhibitors among the derivatives that were initially evaluated were (2E)-N-(3-chlorophenyl)-3-phenylprop-2-enamide (2c) and (2E)-N-(3-bromophenyl)-3-phenylprop-2-enamide (2d) with IC50 values of 0.53 μM and 0.45 μM, respectively. These derivatives exhibited reversible and selective Inhibition of MAO-B with binding affinities 37 fold higher for MAO-B than for MAO-A. Analysis of the possible binding interactions of these inhibitors with active site models of human MAO-A and –B led to the design of phenolic and benzonitrile derivatives of 2c and 2d. Among these were (2E)-N-(3-chlorophenyl)-3-(4-hydroxyphenyl)prop-2-enamide (7c) and (2E)-N-(3-bromophenyl)-3-(4-hydroxyphenyl)prop-2-enamide (7d) which inhibited MAO-B selectively and reversibly with IC50 values of 0.032 μM and 0.026 μM, respectively. These inhibitors were at least 14 fold more potent than 2c and 2d. This study concludes that N,3-diphenylprop-2-enamide is a suitable scaffold for the design of selective MAO-B inhibitors and structural modifications to enhance the binding affinities of the inhibitors for the MAO-B active site include substitution with halogens on the N-phenyl ring and substitution with hydroxyl and nitrile functional groups on the para and meta positions, respectively, of the C3 phenyl ring. Possible binding modes of these structures within the MAO-B active site are proposed with the emphasis on the interactions of the inhibitor halogens and the hydroxyl and nitrile functional groups with active site residues and water molecules.

Hitoshi Okamura - One of the best experts on this subject based on the ideXlab platform.

Kunio Kitahama - One of the best experts on this subject based on the ideXlab platform.

Andrea H. Weinberger - One of the best experts on this subject based on the ideXlab platform.

  • Monoamine Oxidase Inhibition for Tobacco Pharmacotherapy
    Clinical pharmacology and therapeutics, 2007
    Co-Authors: Tony P. George, Andrea H. Weinberger
    Abstract:

    Tobacco addiction is the most significant preventable cause of morbidity and mortality in the Western world, with over 430,000 deaths annually from tobacco-related disease in the United States [1]. While effective treatments are available for smoking cessation (e.g. nicotine replacement therapies, sustained-release bupropion and varenicline), they do not work for all smokers. Thus, the development of more effective medications for smoking cessation based on novel mechanisms is a high priority [2]. This article reviews the links between smoking and Monoamine Oxidase Inhibition towards the development of novel tobacco pharmacotherapies.

Andrew Holt - One of the best experts on this subject based on the ideXlab platform.

  • On the practical aspects of characterising Monoamine Oxidase Inhibition in vitro
    Journal of Neural Transmission, 2018
    Co-Authors: Andrew Holt
    Abstract:

    The development of novel inhibitors of human Monoamine Oxidase enzymes with improved pharmacodynamic and pharmacokinetic profiles has, in the past, been hampered by limited access to enzyme, by assay protocols offering limited throughput, and by inappropriate analyses of kinetic data. More recently, high-level expression of human enzymes in yeast has facilitated thorough examinations of steady-state enzyme behaviour that have led to improvements in our understanding of the mathematical underpinnings of kinetic analyses of Monoamine Oxidases. However, with these improvements have come a realisation that to be useful, more data points across wider concentration ranges are required. In turn, many discontinuous assay approaches, such as those involving radiolabelled substrates or chromatographic separation of product from substrate, have been rendered somewhat obsolete. Justification for the use of a platereader-based approach to assess the effects of novel inhibitors on monamine Oxidases is provided, along with details of experimental design optimised to address the unexpectedly complex kinetics followed by these enzymes. Potential sources of error are discussed, and comments provided on techniques that may enhance the quality of experimental data.