An update on amine oxidase inhibitors: Multifaceted drugs

Song, Mee-Sook; Matveychuk, Dmitriy; MacKenzie, Erin M.; Duchcherer, Maryana; Mousseau, Darrell D.; Baker, Glen B.

doi:10.1016/j.pnpbp.2013.02.001

Cited by 82 publications

(50 citation statements)

References 111 publications

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“…The propargyl group is also found in other drugs used to treat nervous system diseases, such as rasagiline, selegiline, pargyline, ladostigil, and clorgyline (Potashman and Duggan 2009;Song et al, 2013). However, the role of the propargyl group in their distribution profiles has never been discussed.…”

Section: Discussionmentioning

confidence: 99%

P-Retigabine: An N-Propargyled Retigabine with Improved Brain Distribution and Enhanced Antiepileptic Activity

Zhou

Zhang

et al. 2014

Mol Pharmacol

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Retigabine (RTG,methyl] amino] phenyl] carbamate]) is a first-in-class antiepileptic drug that acts by potentiating neuronal KCNQ potassium channels; however, it has less than optimal brain distribution. In this study, we report that P-RTG (ethyl N-[2-amino-4-((4-fluorobenzyl) (prop-2-ynyl)amino)phenyl]carbamate), an RTG derivative that incorporates a propargyl group at the N position of the RTG linker, exhibits an inverted brain distribution compared with RTG. The brain-to-plasma concentration ratio of P-RTG increased to 2.30 compared with 0.16 for RTG. However, the structural modification did not change the drug's potentiation potency, subtype selectivity, or RTG molecular determinants on KCNQ channels. In addition, in cultured hippocampal neurons, P-RTG exhibited a similar capability as RTG for suppressing both induced and spontaneous action potential firing. Notably, P-RTG antiepileptic activity in the maximal electroshock (MES)-induced mouse seizure model was significantly enhanced to a value 2.5 times greater than that of RTG. Additionally, the neurotoxicity of P-RTG in the rotarod test was comparable with that of RTG. Collectively, our results indicate that the incorporation of a propargyl group significantly improves the RTG brain distribution, supporting P-RTG as a promising antiepileptic drug candidate. The strategy for improving brain-to-plasma distribution of RTG might be applicable for the drug development of other central nervous system diseases.

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Section: Discussionmentioning

confidence: 99%

P-Retigabine: An N-Propargyled Retigabine with Improved Brain Distribution and Enhanced Antiepileptic Activity

Zhou

Zhang

et al. 2014

Mol Pharmacol

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“…Its inhibitors, used as antidepressant drugs for over 50 years, have been shown to raise brain amine levels. The observation that inhibition of MAO increases monoaminergic function has supported a long-running drug discovery effort to find novel drugs that inhibit MAO to treat mood and degenerative disorders, including depression, aggression, schizophrenia, hyperactivity, Parkinson's Disease (PD), and Alzheimer's Disease (AD) (Oreland, 2004, Murphy et al, 2006, Oreland et al, 2007, Fisar et al, 2010, Bortolato and Shih, 2011, Song et al, 2013.…”

Section: Introductionmentioning

confidence: 99%

“…The interest in drug design to increase monoamine levels is reflected in a constant stream of reviews. Several reviews in the last 5 years provide the wider background to MAO (Bortolato and Shih, 2011, Youdim and Reiderer, 2011, Ramsay, 2012, Song et al, 2013, Fowler et al, 2015 This review will include key references for the established facts but focus on examples of recent research on the expression, activity and inhibition of MAO B.…”

Section: Introductionmentioning

confidence: 99%

Molecular aspects of monoamine oxidase B

Ramsay

2016

Progress in Neuro-Psychopharmacology and Biological Psychiatry

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Graphical abstract Highlights• MAO B activity depends on both amine and oxygen concentrations KeywordsMonoamine oxidase B; kinetics; drug design; neurotransmitter levels; platelet AbbreviationsAlzheimer's Disease, AD; Parkinson's Disease, PD; dopamine transporter, DAT; serotonin transporter, SERT; noradrenaline transporter, NET; the vesicular transporter, VMAT; Gprotein coupled receptor, GPCR; induced pluripotent stem cells, iPSC; serotonin reuptake inhibitor, SSRI; brain-derived neurotrophic factor, BDNF; multi-target designed ligands, MTDL; IC 50 , the concentration of compound required to inhibit a specified assay by 50%; K i , a kinetically measured inhibitor dissociation constant. Word count -approx 5490 (excluding references). Abstract 196 words.3

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“…For more than half century, MAOs have been recognized as major contributors to the pathogenesis of human neurodegenerative and depressive disorders, and both irreversible and reversible pharmacological inhibitors have unequivocally proven their therapeutical properties in these settings (Al-Nuaimi et al 2012;Song et al 2013;Youdim et al 2006).…”

Section: Introductionmentioning

confidence: 99%

Monoamine oxidases are novel sources of cardiovascular oxidative stress in experimental diabetes

Sturza

Duicu

Văduva

et al. 2015

Can. J. Physiol. Pharmacol.

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Diabetes mellitus (DM) is widely recognized as the most severe metabolic disease associated with increased cardiovascular morbidity and mortality. The generation of reactive oxygen species (ROS) is a major event causally linked to the development of cardiovascular complications throughout the evolution of DM. Recently, monoamine oxidases (MAOs) at the outer mitochondrial membrane, with 2 isoforms, MAO-A and MAO-B, have emerged as novel sources of constant hydrogen peroxide (H2O2) production in the cardiovascular system via the oxidative deamination of biogenic amines and neurotransmitters. Whether MAOs are mediators of endothelial dysfunction in DM is unknown, and so we studied this in a streptozotocin-induced rat model of diabetes. MAO expression (mRNA and protein) was increased in both arterial samples and hearts isolated from the diabetic animals. Also, H2O2 production (ferrous oxidation - xylenol orange assay) in aortic samples was significantly increased, together with an impairment of endothelium-dependent relaxation (organ-bath studies). MAO inhibitors (clorgyline and selegiline) attenuated ROS production by 50% and partially normalized the endothelium-dependent relaxation in diseased vessels. In conclusion, MAOs, in particular the MAO-B isoform, are induced in aortas and hearts in the streptozotocin-induced diabetic rat model and contribute, via the generation of H2O2, to the endothelial dysfunction associated with experimental diabetes.

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An update on amine oxidase inhibitors: Multifaceted drugs

Cited by 82 publications

References 111 publications

P-Retigabine: An N-Propargyled Retigabine with Improved Brain Distribution and Enhanced Antiepileptic Activity

P-Retigabine: An N-Propargyled Retigabine with Improved Brain Distribution and Enhanced Antiepileptic Activity

Molecular aspects of monoamine oxidase B

Monoamine oxidases are novel sources of cardiovascular oxidative stress in experimental diabetes

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