Monoamine Oxidase Inhibitors—Revisiting a Therapeutic Principle

Entzeroth, Michael; Ratty, Anil K.

doi:10.4236/ojd.2017.62004

Cited by 32 publications

(22 citation statements)

References 182 publications

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“…4 E). The phenotypic similarity between these drugs is consistent with the fact that MOAI inhibits serotonin metabolism resulting in its accumulation and activation of serotonin receptors in what is known as serotonin syndrome 27 , 28 . Therefore, combining phenotypic and structural similarity can facilitate the determination of the likely affected mechanism of action of a drug in a specific biological context.…”

Section: Resultssupporting

confidence: 66%

Morphological landscape of endothelial cell networks reveals a functional role of glutamate receptors in angiogenesis

Sailem

Zen

2020

Sci Rep

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Angiogenesis plays a key role in several diseases including cancer, ischemic vascular disease, and Alzheimer's disease. chemical genetic screening of endothelial tube formation provides a robust approach for identifying signalling components that impact microvascular network morphology as well as endothelial cell biology. However, the analysis of the resulting imaging datasets has been limited to a few phenotypic features such as the total tube length or the number of branching points. Here we developed a high content analysis framework for detailed quantification of various aspects of network morphology including network complexity, symmetry and topology. By applying our approach to a high content screen of 1,280 characterised drugs, we found that drugs that result in a similar phenotype share the same mechanism of action or common downstream signalling pathways. our multiparametric analysis revealed that a group of glutamate receptor antagonists enhances branching and network connectivity. Using an integrative meta-analysis approach, we validated the link between these receptors and angiogenesis. We further found that the expression of these genes is associated with the prognosis of Alzheimer's patients. In conclusion, our work shows that detailed image analysis of complex endothelial phenotypes can reveal new insights into biological mechanisms modulating the morphogenesis of endothelial networks and identify potential therapeutics for angiogenesis-related diseases. The primary function of microvascular networks across the body is to provide nutrients and oxygen supply for tissues. Both the vasculogenic and angiogenic processes are coordinated to form the network of tissue microvasculature. Vasculogenesis is the de novo formation of vessels from the assembly of progenitors or mature endothelial aggregates 1. While in angiogenesis, the new vessels are formed from pre-existing ones 2. Endothelial cell branching and tubulogenesis are critical elements for the formation of functional microvascular networks during embryonic development and postnatal life. Defects in vascular network structure or formation play a significant role in many pathological conditions, including ischemic vascular disease, cancer, neurodegenerative diseases, inflammatory disorders, and diabetes 3. Consequently, the identification of small molecules or signalling components that regulate this complex process has important implications for many diseases. The features of the nascent endothelial network are determined by genetic components and the surrounding microenvironment. Changes in these factors can affect vessel morphology, structure, organisation, or permeability leading to different pathologies 3,4. For instance, the vessels that are formed in tumours are often abnormal and can have various phenotypes, including irregular organisation, loosely assembled vessel wall, abnormally wide or thin vessels, and tortuous serpentine-like morphology 4. On the other hand, leaky vessels have been observed in diabetic retinopathy and neurodegenerativ...

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Section: Resultssupporting

confidence: 66%

Morphological landscape of endothelial cell networks reveals a functional role of glutamate receptors in angiogenesis

Sailem

Zen

2020

Sci Rep

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“…3E). The phenotypic similarity between these drugs is consistent with the fact that MOAI inhibits serotonin metabolism resulting in its accumulation and activation of serotonin receptors in what is known as serotonin syndrome (Boyer and Shannon, 2005;Entzeroth and Ratty, 2017). Therefore, combining phenotypic and structural similarity can facilitate the determination of the likely affected mechanism of action of a drug in a specific biological context.…”

Section: Identifying Multi-dimensional Phenotypic Signatures Of Endotsupporting

confidence: 53%

Multi-Parametric Profiling of Endothelial Cell Networks Reveals Functional Role of Glutamate Receptors in Angiogenesis

Sailem

Zen

2019

Preprint

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Angiogenesis plays a key role in several diseases including cancer, ischemic vascular disease, and Alzheimer's disease. High throughput screening of endothelial tube formation provides a robust approach for identifying drugs that impact microvascular network formation and morphology. However, the analysis of resulting imaging datasets has been limited to a few phenotypic features such as the total tube length or the number of branching points. Here we developed a high content analysis framework for detailed quantification of various aspects of network morphology including network complexity, symmetry and topology. By applying our approach to a high content screen of 1,280 drugs, we found that many drugs that result in a similar phenotype share the same mechanism of action or common downstream signalling pathways. Our multiparametric analysis revealed a group of drugs, that target glutamate receptors, results in enhanced branching and network connectivity. Using an integrative meta-analysis approach, we validated the link between these receptors and angiogenesis. We further found that the expression of these genes correlates with the prognosis of Alzheimer's patients. In conclusion, our work shows that detailed image analysis of complex endothelial phenotypes can reveal new insights into biological mechanisms modulating the morphogenesis of endothelial networks and identify potential therapeutics for angiogenesisrelated diseases.

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“…However, the X‐ray crystallographic structures of MAO‐B in complex with several small molecule inhibitors and the development of pharmacophore models for MAO‐BIs facilitated a deeper understanding of features required for inhibitor potency, and also greatly assisted in structure‐based inhibitor/drug design. Since then, much attention has been paid to the design and synthesis of potent and selective MAO‐BIs …”

Section: Development Of Pharmacophore Model For Maoismentioning

confidence: 99%

Monoamine oxidase‐B inhibitors as potential neurotherapeutic agents: An overview and update

Tripathi

Ayyannan

2019

Medicinal Research Reviews

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Monoamine oxidase (MAO) inhibitors have made significant contributions and remain an indispensable approach of molecular and mechanistic diversity for the discovery of antineurodegenerative drugs. However, their usage has been hampered by nonselective and/or irreversible action which resulted in drawbacks like liver toxicity, cheese effect, and so forth. Hence, the search for selective MAO inhibitors (MAOIs) has become a substantial focus in current drug discovery. This review summarizes our current understanding on MAO‐A/MAO‐B including their structure, catalytic mechanism, and biological functions with emphases on the role of MAO‐B as a potential therapeutic target for the development of medications treating neurodegenerative disorders. It also highlights the recent developments in the discovery of potential MAO‐B inhibitors (MAO‐BIs) belonging to diverse chemical scaffolds, arising from intensive chemical‐mechanistic and computational studies documented during past 3 years (2015‐2018), with emphases on their potency and selectivity. Importantly, readers will gain knowledge of various newly established MAO‐BI scaffolds and their development potentials. The comprehensive information provided herein will hopefully accelerate ideas for designing novel selective MAO‐BIs with superior activity profiles and critical discussions will inflict more caution in the decision‐making process in the MAOIs discovery.

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Monoamine Oxidase Inhibitors—Revisiting a Therapeutic Principle

Cited by 32 publications

References 182 publications

Morphological landscape of endothelial cell networks reveals a functional role of glutamate receptors in angiogenesis

Morphological landscape of endothelial cell networks reveals a functional role of glutamate receptors in angiogenesis

Multi-Parametric Profiling of Endothelial Cell Networks Reveals Functional Role of Glutamate Receptors in Angiogenesis

Monoamine oxidase‐B inhibitors as potential neurotherapeutic agents: An overview and update

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