Synthesis of a series of unsaturated ketone derivatives as selective and reversible monoamine oxidase inhibitors

Choi, Ji Won; Jang, Bo Ko; Cho, Nam Chul; Park, Jong Hyun; Yeon, Seul Ki; Ju, Eun Ji; Lee, Yong Sup; Han, Gyoonhee; Pae, Ae Nim; Kim, Dong Jin; Park, Ki Duk

doi:10.1016/j.bmc.2015.08.012

Cited by 80 publications

(50 citation statements)

References 31 publications

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“…Concerning ciproxifan, which displays IC 50 values for both hMAO isoforms only in a micromolar range, we found its inhibition far too low for therapeutic efficacy in humans, which is anyway limited by its low affinity at human H3R. For example, safinamide, a MAO B selective reversible inhibitor most recently approved as first add-on treatment of Parkinson’s disease, is active in submicromolar concentration ranges (IC 50 = 0.048–0.112 μM for hMAO B; IC 50, MAO B /IC 50, MAO A < 0.001202122). Additionally, imidazole-containing drugs like ciproxifan are potential inhibitors of cytochrome P450 enzymes by coordination of the heme iron atom23.…”

Section: Discussionmentioning

confidence: 98%

Ciproxifan, a histamine H3 receptor antagonist, reversibly inhibits monoamine oxidase A and B

Hagenow

Stasiak

Ramsay

et al. 2017

Sci Rep

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Ciproxifan is a well-investigated histamine H3 receptor (H3R) inverse agonist/antagonist, showing an exclusively high species-specific affinity at rodent compared to human H3R. It is well studied as reference compound for H3R in rodent models for neurological diseases connected with neurotransmitter dysregulation, e.g. attention deficit hyperactivity disorder or Alzheimer’s disease. In a screening for potential monoamine oxidase A and B inhibition ciproxifan showed efficacy on both enzyme isoforms. Further characterization of ciproxifan revealed IC50 values in a micromolar concentration range for human and rat monoamine oxidases with slight preference for monoamine oxidase B in both species. The inhibition by ciproxifan was reversible for both human isoforms. Regarding inhibitory potency of ciproxifan on rat brain MAO, these findings should be considered, when using high doses in rat models for neurological diseases. As the H3R and monoamine oxidases are all capable of affecting neurotransmitter modulation in brain, we consider dual targeting ligands as interesting approach for treatment of neurological disorders. Since ciproxifan shows only moderate activity at human targets, further investigations in animals are not of primary interest. On the other hand, it may serve as starting point for the development of dual targeting ligands.

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Section: Discussionmentioning

confidence: 98%

Ciproxifan, a histamine H3 receptor antagonist, reversibly inhibits monoamine oxidase A and B

Hagenow

Stasiak

Ramsay

et al. 2017

Sci Rep

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“…[14] Many studies have shown that these scaffoldsh ave selectivea nd reversible/ irreversible MAO-B inhibitory activity in the nanomolar range. [15][16][17][18][19][20][21] Prior studies revealed that the removal of the double bond system in chalcone leads to decreased activity in MAO inhibition. [22,23] Additionally,h eterocyclic substituents such as furan, chromene, thiophene, piperidine, quinoline, and indole in the chalcone scaffold lead to improved MAO inhibition.…”

mentioning

confidence: 99%

Monoamine Oxidase Inhibitory Activity: Methyl‐ versus Chlorochalcone Derivatives

Mathew

Uçar

Mathew³

et al. 2016

ChemMedChem

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Numerous studies have shown that chalcones are promising scaffolds for the development of new monoamine oxidase-B (MAO-B) inhibitors. As a continuation of our ongoing research into the development of reversible human MAO-B (hMAO-B) inhibitors, two series of twenty chalcones containing electron-donating and electron-withdrawing substituents were synthesized. All compounds were found to be competitive, selective, and reversible inhibitors of hMAO-B except (2E)-1-(4-methylphenyl)-3-(4-nitrophenyl)prop-2-en-1-one (P7) and (2E)-1-(4-chlorophenyl)-3-(4-nitrophenyl)prop-2-en-1-one (P17), which were found to be selective inhibitors of hMAO-A. The most potent hMAO-B inhibitor, (2E)-1-(4-chlorophenyl)-3-(4-ethylphenyl)prop-2-en-1-one (P16), showed a K value of 0.11±0.01 μm. Molecular docking simulations were carried out to identify the hypothetical binding mode for the most potent compounds in the active sites of hMAO-A and B. The ability of the compounds to cross the blood-brain barrier was assessed by parallel artificial membrane permeability assay (PAMPA). Additionally, the most potent hMAO-B inhibitor P16 showed no toxicity in cultured hepatic cells at concentrations of 5 and 25 μm.

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“…Since increased PLA2 activity has been associated with neuropsychiatric disorders and inhibitors of PLA2 have been shown to be effective against amyloid beta peptide-induced apoptosis in primary neuronal cultures (24), it may be that PLA2 inhibition is part of the mechanism of action of these three MnMs in providing protection in the cellular disease models tested here. 4′-Hydroxychalcone is also a monoamine oxidase (MAO) inhibitor (25), which may help to preserve mitochondrial health under disease conditions. MAO resides in the mitochondrial outer membrane and produces hydrogen peroxide by oxidation of monoamine substrates to increase oxidative stress.…”

Section: Discussionmentioning

confidence: 99%

Neuron-based high-content assay and screen for CNS active mitotherapeutics

et al. 2020

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Impaired mitochondrial dynamics and function are hallmarks of many neurological and psychiatric disorders, but direct screens for mitotherapeutics using neurons have not been reported. We developed a multiplexed and high-content screening assay using primary neurons and identified 67 small-molecule modulators of neuronal mitostasis (MnMs). Most MnMs that increased mitochondrial content, length, and/or health also increased mitochondrial function without altering neurite outgrowth. A subset of MnMs protected mitochondria in primary neurons from Aβ(1–42) toxicity, glutamate toxicity, and increased oxidative stress. Some MnMs were shown to directly target mitochondria. The top MnM also increased the synaptic activity of hippocampal neurons and proved to be potent in vivo, increasing the respiration rate of brain mitochondria after administering the compound to mice. Our results offer a platform that directly queries mitostasis processes in neurons, a collection of small-molecule modulators of mitochondrial dynamics and function, and candidate molecules for mitotherapeutics.

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Synthesis of a series of unsaturated ketone derivatives as selective and reversible monoamine oxidase inhibitors

Cited by 80 publications

References 31 publications

Ciproxifan, a histamine H3 receptor antagonist, reversibly inhibits monoamine oxidase A and B

Ciproxifan, a histamine H3 receptor antagonist, reversibly inhibits monoamine oxidase A and B

Monoamine Oxidase Inhibitory Activity: Methyl‐ versus Chlorochalcone Derivatives

Neuron-based high-content assay and screen for CNS active mitotherapeutics

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