Kinetic and structural analysis of the irreversible inhibition of human monoamine oxidases by ASS234, a multi-target compound designed for use in Alzheimer's disease

Esteban, Gerard; Allan, Jennifer; Samadi, Abdelouahid; Mattevi, Andrea; Unzeta, Mercedes; Marco‐Contelles, José; Binda, Claudia; Ramsay, Rona R.

doi:10.1016/j.bbapap.2014.03.006

Cited by 48 publications

(66 citation statements)

References 43 publications

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“…Inspection of the UV-visible spectrum of F2MPA-inactivated MAO B showed the same modified flavin peak (data not shown) encountered with other propargyl inhibitors such as deprenyl [29][30] , which suggested that F2MPA may form a similar covalent adduct with the hMAO B cofactor. The crystal structure of hMAO B in complex with F2MPA was solved at 2.4 Å.…”

Section: Characterization Of Hmao a And Hmao B Inhibition By F2mpamentioning

confidence: 94%

“…The crystal structure of hMAO B in complex with F2MPA was solved at 2.4 Å. The electron density map of the inhibitor is continuous with that of the FAD cofactor, indicating that the flavin N5 atom reacted with the propargyl unit of the compound forming a covalent adduct ( Figure 3A) which resembles those found for all the other inhibitors of this class 30 . Although F2MPA is identically bound in either of the two protein molecules that occupy the asymmetric unit (rmsd = 0.27 Å), the adduct is slightly better defined in subunit B and we will refer to it for the following discussion.…”

Section: Characterization Of Hmao a And Hmao B Inhibition By F2mpamentioning

confidence: 99%

“…Both hMAO A and hMAO B were produced as recombinant enzymes using yeast expression systems and purified as previously described [29][30] . Spectrophotometric and fluorimetric methods were used for enzymatic assays on both hMAO A and hMAO B to characterize F2MPA inhibition properties.…”

Section: Inhibition Studiesmentioning

confidence: 99%

“…For rat tissue experiments, inactivation parameters (k inact and K I ) were determined as described previously 28,30 . Rat liver homogenate was prepared from frozen rat liver at 1g in 5 mL of 50 mM potassium phosphate, pH 7.5, containing 0.2% Triton X-100.…”

Section: Inhibition Studiesmentioning

confidence: 99%

“…X-ray diffraction data were collected at the X06SA beamline of SLS synchrotron (Villigen, Switzerland), which were processed by MOSFLM 36 and CCP4 programs 37 . Model building by Coot 38 and refinement by Refmac5 39 were carried out using standard protocols 30 . Statistics are reported in Table 3 and figures were produced using CCP4mg 40 .…”

Section: X-ray Crystallographymentioning

confidence: 99%

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Comparative Analysis of the Neurochemical Profile and MAO Inhibition Properties of N-(Furan-2-ylmethyl)-N-methylprop-2-yn-1-amine

Deurwaerdère

Binda

Corne

et al. 2016

ACS Chem. Neurosci.

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The regulation of brain monoamine levels is paramount for cognitive functions and the enzymes monoamine oxidases (MAO A and B) play a central role in these processes. The aim of this study was to evaluate whether the pro-cognitive properties exerted by propargylamine N-(furan-2-ylmethyl)-N-methylprop-2-yn-1-amine (F2MPA) were related to changes in monoamine content via MAO inhibition. In vivo microdialysis and ex vivo amine metabolite measurement demonstrated region-specific alterations in monoamine metabolism that differ from both the classic MAO A or MAO B inhibitors clorgyline and L-deprenyl, respectively. Although all the inhibitors (1 and 4 mg/kg) increased cortical serotonin tissue content, only F2MPA increased the levels of cortical noradrenaline. In the striatum, clorgyline (1 mg/kg), but not F2MPA (1 mg/kg), reduced extracellular levels of dopamine metabolites at rest or stimulated by the intrastriatal application of the MAO substrate 3-methoxytyramin. In vitro, F2MPA exhibited a low affinity toward MAO B and MAO A. Nonetheless, it modified the B form of MAO, forming a flavin adduct structurally similar to that with deprenyl. F2MPA was rapidly metabolized in the presence of rat, but not human, microsomes, producing a hydroxylated derivative. In conclusion, the effect of F2MPA on cognition may arise from monoaminergic changes in the cortex, but the role of MAO in this process is likely to be negligible, consistently to the F2MPA poor affinity for MAO.

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Section: Characterization Of Hmao a And Hmao B Inhibition By F2mpamentioning

confidence: 94%

Section: Characterization Of Hmao a And Hmao B Inhibition By F2mpamentioning

confidence: 99%

Section: Inhibition Studiesmentioning

confidence: 99%

Section: Inhibition Studiesmentioning

confidence: 99%

Section: X-ray Crystallographymentioning

confidence: 99%

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Comparative Analysis of the Neurochemical Profile and MAO Inhibition Properties of N-(Furan-2-ylmethyl)-N-methylprop-2-yn-1-amine

Deurwaerdère

Binda

Corne

et al. 2016

ACS Chem. Neurosci.

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Enzymes Processing Neurotransmitters

2019

Chemical Biology of Neurodegeneration

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Multipotente Liganden mit kombinierter Cholinesterase‐ und Monoaminooxidase‐Inhibition sowie Histamin‐H₃R‐Antagonismus bei neurodegenerativen Erkrankungen

et al. 2017

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Die Therapie von komplexen neurodegenerativen Erkrankungen erfordert eine Entwicklung von Multitargetorientierten Wirkstoffen. Durchs trukturelle Optimierung des neuroprotektiven Liganden ASS234 mittels Integration etablierter Pharmakophore des Histamin-H 3 -Rezeptors (H3R) konnten neuartige Indolderivate mit inhibitorischer Aktivität an Acetylcholin-/Butyrylcholinesterasen und Monoaminooxidasen Aund BsowieamH3R erzielt werden. Diese zeigten ein ausbalanciertes Wirkprofil an den gewünschten Targets in zumeist nanomolaren Konzentrationsbereichen. Weiterführende In-vitro-Untersuchungen zeigten antioxidative und neuroprotektive Fähigkeiten sowie die Überwindung der Blut-Hirn-Schranke.M it diesem vielversprechenden Wirkprofil zeigte Contilisant (bei 1mgkg À1 i.p.) eine signifikante Verbesserung von Lipopolysaccharid-induzierten kognitiven Defiziten. Morbus Alzheimer und Morbus Parkinson zählen zu den häufigsten neurodegenerativen Erkrankungen, welche durch komplexe und vielfältige Mechanismen gekennzeichnet sind. Bei der Suche nach mçglichen Krankheitsursachen sowie effizienteren Therapieoptionen stellten sich mitochondriale Dysfunktionen, Neuroinflammation und oxidativer Stress als Schlüsselfaktoren bei der Entstehung und dem Fortschreiten dieser Erkrankungen heraus.Folglich ist die Entwicklung von antioxidativen Wirkstoffstrategien fürd iese Erkrankungen, insbesondere fürM orbus Alzheimer,v on großer Bedeutung. [1,2] Der kürzlich beschriebene Multitarget-orientierten Ligand (MTL) ASS234 (Abbildung 1) [3][4][5] zeigt eine irreversible Hemmung der Monoaminooxidasen Aund B(MAOA/ B) und reduziert die Entstehung des Sekundärproduktes Wasserstoffperoxid, eine reaktive Sauerstoffspezies (ROS). [6] Dies führt zum einen zur Verminderung der katalytischen Oxidation von biogenen Aminen, wie Serotonin (5-HT), Norepinephrin und Dopamin, die an kognitiven Prozessen beteiligt sind, und zum anderen zur verminderten Erzeugung von ROS, die zum neuronalen Zelltod führen kçnnen. ASS234 zeigt zusätzlich eine reversible Inhibition von Ace-[*] S. Hagenow, [+] J.

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Kinetic and structural analysis of the irreversible inhibition of human monoamine oxidases by ASS234, a multi-target compound designed for use in Alzheimer's disease

Cited by 48 publications

References 43 publications

Comparative Analysis of the Neurochemical Profile and MAO Inhibition Properties of N-(Furan-2-ylmethyl)-N-methylprop-2-yn-1-amine

Comparative Analysis of the Neurochemical Profile and MAO Inhibition Properties of N-(Furan-2-ylmethyl)-N-methylprop-2-yn-1-amine

Enzymes Processing Neurotransmitters

Multipotente Liganden mit kombinierter Cholinesterase‐ und Monoaminooxidase‐Inhibition sowie Histamin‐H₃R‐Antagonismus bei neurodegenerativen Erkrankungen

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Kinetic and structural analysis of the irreversible inhibition of human monoamine oxidases by ASS234, a multi-target compound designed for use in Alzheimer's disease

Cited by 48 publications

References 43 publications

Comparative Analysis of the Neurochemical Profile and MAO Inhibition Properties of N-(Furan-2-ylmethyl)-N-methylprop-2-yn-1-amine

Comparative Analysis of the Neurochemical Profile and MAO Inhibition Properties of N-(Furan-2-ylmethyl)-N-methylprop-2-yn-1-amine

Enzymes Processing Neurotransmitters

Multipotente Liganden mit kombinierter Cholinesterase‐ und Monoaminooxidase‐Inhibition sowie Histamin‐H3R‐Antagonismus bei neurodegenerativen Erkrankungen

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Product

Resources

About

Multipotente Liganden mit kombinierter Cholinesterase‐ und Monoaminooxidase‐Inhibition sowie Histamin‐H₃R‐Antagonismus bei neurodegenerativen Erkrankungen