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The FEBS Journal Aug 2015Cyclopropylamines, inhibitors of monoamine oxidases (MAO) and lysine-specific demethylase (LSD1), provide a useful structural scaffold for the design of mechanism-based...
Cyclopropylamines, inhibitors of monoamine oxidases (MAO) and lysine-specific demethylase (LSD1), provide a useful structural scaffold for the design of mechanism-based inhibitors for treatment of depression and cancer. For new compounds with the less common cis relationship and with an alkoxy substituent at the 2-position of the cyclopropyl ring, the apparent affinity determined from docking experiments revealed little difference between the enantiomers. Using the racemate, kinetic parameters for the reversible and irreversible inhibition of MAO were determined. No inhibition of LSD1 was observed. For reversible inhibition, most compounds gave high IC50 values with MAO A, but sub-micromolar values with MAO B. After pre-incubation of the cyclopropylamine with the enzyme, the inhibition was irreversible for both MAO A and MAO B, and the activity was not restored by dilution. Spectral changes during inactivation of MAO A included bleaching at 456 nm and an increased absorbance at 400 nm, consistent with flavin modification. These derivatives are MAO B-selective irreversible inhibitors that do not show inhibition of LSD1. The best inhibitor was cis-N-benzyl-2-methoxycyclopropylamine, with an IC50 of 5 nm for MAO B and 170 nm for MAO A after 30 min pre-incubation. This cis-cyclopropylamine is over 20-fold more effective than tranylcypromine, so may be studied as a lead for selective inhibitors of MAO B that do not inhibit LSD1.
Topics: Antidepressive Agents; Catalytic Domain; Cyclopropanes; Histone Demethylases; Humans; In Vitro Techniques; Kinetics; Models, Molecular; Monoamine Oxidase; Monoamine Oxidase Inhibitors; Stereoisomerism; Structure-Activity Relationship; Tranylcypromine
PubMed: 25755053
DOI: 10.1111/febs.13260 -
Cells Aug 2020Monoamine oxidase (MAO) has been implicated in neuroinflammation, and therapies targeting MAO are of interest for neurodegenerative diseases. The small-molecule drug...
Monoamine oxidase (MAO) has been implicated in neuroinflammation, and therapies targeting MAO are of interest for neurodegenerative diseases. The small-molecule drug tranylcypromine, an inhibitor of MAO, is currently used as an antidepressant and in the treatment of cancer. However, whether tranylcypromine can regulate LPS- and/or Aβ-induced neuroinflammation in the brain has not been well-studied. In the present study, we found that tranylcypromine selectively altered LPS-induced proinflammatory cytokine levels in BV2 microglial cells but not primary astrocytes. In addition, tranylcypromine modulated LPS-mediated TLR4/ERK/STAT3 signaling to alter neuroinflammatory responses in BV2 microglial cells. Importantly, tranylcypromine significantly reduced microglial activation as well as proinflammatory cytokine levels in LPS-injected wild-type mice. Moreover, injection of tranylcypromine in 5xFAD mice (a mouse model of AD) significantly decreased microglial activation but had smaller effects on astrocyte activation. Taken together, our results suggest that tranylcypromine can suppress LPS- and Aβ-induced neuroinflammatory responses in vitro and in vivo.
Topics: Alzheimer Disease; Animals; Disease Models, Animal; Humans; Inflammation; Lipopolysaccharides; Mice; Monoamine Oxidase Inhibitors; Tranylcypromine
PubMed: 32872335
DOI: 10.3390/cells9091982 -
International Journal of Molecular... May 2023Alzheimer's disease (AD) is a complex disease with an unknown etiology. Available treatments, limited to cholinesterase inhibitors and -methyl-d-aspartate receptor...
Alzheimer's disease (AD) is a complex disease with an unknown etiology. Available treatments, limited to cholinesterase inhibitors and -methyl-d-aspartate receptor (NMDAR) antagonists, provide symptomatic relief only. As single-target therapies have not proven effective, rational specific-targeted combination into a single molecule represents a more promising approach for treating AD, and is expected to yield greater benefits in alleviating symptoms and slowing disease progression. In the present study, we designed, synthesized, and biologically evaluated 24 novel -methylpropargylamino-quinazoline derivatives. Initially, compounds were thoroughly inspected by in silico techniques determining their oral and CNS availabilities. We tested, in vitro, the compounds' effects on cholinesterases and monoamine oxidase A/B (MAO-A/B), as well as their impacts on NMDAR antagonism, dehydrogenase activity, and glutathione levels. In addition, we inspected selected compounds for their cytotoxicity on undifferentiated and differentiated neuroblastoma SH-SY5Y cells. We collectively highlighted as the best candidate endowed with a selective MAO-B inhibition profile, NMDAR antagonism, an acceptable cytotoxicity profile, and the potential to permeate through BBB. The structure-guided drug design strategy applied in this study imposed a novel concept for rational drug discovery and enhances our understanding on the development of novel therapeutic agents for treating AD.
Topics: Humans; Alzheimer Disease; Monoamine Oxidase Inhibitors; Neuroblastoma; Cholinesterase Inhibitors; Monoamine Oxidase; Drug Design; Acetylcholinesterase; Structure-Activity Relationship
PubMed: 37298087
DOI: 10.3390/ijms24119124 -
Molecules (Basel, Switzerland) Jul 2022Monoamine oxidase inhibitors (MAOIs) are an important class of drugs prescribed for treatment of depression and other neurological disorders. Evidence has suggested that... (Review)
Review
Monoamine oxidase inhibitors (MAOIs) are an important class of drugs prescribed for treatment of depression and other neurological disorders. Evidence has suggested that patients with atypical depression preferentially respond to natural product MAOIs. This review presents a comprehensive survey of the natural products, predominantly from plant sources, as potential new MAOI drug leads. The psychoactive properties of several traditionally used plants and herbal formulations were attributed to their MAOI constituents. MAO inhibitory constituents may also be responsible for neuroprotective effects of natural products. Different classes of MAOIs were identified from the natural product sources with non-selective as well as selective inhibition of MAO-A and -B. Selective reversible natural product MAOIs may be safer alternatives to the conventional MAOI drugs. Characterization of MAO inhibitory constituents of natural products traditionally used as psychoactive preparations or for treatment of neurological disorders may help in understanding the mechanism of action, optimization of these preparations for desired bioactive properties, and improvement of the therapeutic potential. Potential therapeutic application of natural product MAOIs for treatment of neuroblastoma is also discussed.
Topics: Biological Products; Humans; Monoamine Oxidase; Monoamine Oxidase Inhibitors; Nervous System Diseases; Neuroblastoma; Neuroprotection
PubMed: 35807542
DOI: 10.3390/molecules27134297 -
Experimental Neurology May 2023Monoamine oxidase (MAO) is an enzyme located on the outer mitochondrial membrane that metabolizes amine substrates like serotonin, norepinephrine and dopamine. MAO...
Monoamine oxidase (MAO) is an enzyme located on the outer mitochondrial membrane that metabolizes amine substrates like serotonin, norepinephrine and dopamine. MAO inhibitors (MAOIs) are frequently utilized to treat disorders such as major depression or Parkinson's disease (PD), though their effects on brain mitochondrial bioenergetics are unclear. These studies measured bioenergetic activity in mitochondria isolated from the mouse cortex in the presence of inhibitors of either MAO-A, MAO-B, or both isoforms. We found that only 10 μM clorgyline, the selective inhibitor of MAO-A and not MAO-B, increased mitochondrial oxygen consumption rate in State V(CI) respiration compared to vehicle treatment. We then assessed mitochondrial bioenergetics, reactive oxygen species (ROS) production, and Electron Transport Chain (ETC) complex function in the presence of 0, 5, 10, 20, 40, or 80 μM of clorgyline to determine if this change was dose-dependent. The results showed increased oxygen consumption rates across the majority of respiration states in mitochondria treated with 5, 10, or 20 μM with significant bioenergetic inhibition at 80 μM clorgyline. Next, we assessed mitochondrial ROS production in the presence of the same concentrations of clorgyline in two different states: high mitochondrial membrane potential (ΔΨ) induced by oligomycin and low ΔΨ induced by carbonyl cyanide 4-(trifluoromethoxy)phenylhydrazone (FCCP). There were no changes in ROS production in the presence of 5, 10, 20, or 40 μM clorgyline compared to vehicle after the addition of oligomycin or FCCP. There was a significant increase in mitochondrial ROS in the presence of 80 μM clorgyline after FCCP addition, as well as reduced Complex I and Complex II activities, which are consistent with inhibition of bioenergetics seen at this dose. There were no changes in Complex I, II, or IV activities in mitochondria treated with low doses of clorgyline. These studies shed light on the direct effect of MAO-A inhibition on brain mitochondrial bioenergetic function, which may be a beneficial outcome for those taking these medications.
Topics: Mice; Animals; Monoamine Oxidase; Clorgyline; Carbonyl Cyanide p-Trifluoromethoxyphenylhydrazone; Reactive Oxygen Species; Monoamine Oxidase Inhibitors; Mitochondria; Respiration
PubMed: 36841465
DOI: 10.1016/j.expneurol.2023.114356 -
Future Medicinal Chemistry Jun 2018There is little information available on the monoamine oxidase isoform selectivity of N-alkyl harmine analogs, which exhibit a myriad of activities including MAO-A,...
AIM
There is little information available on the monoamine oxidase isoform selectivity of N-alkyl harmine analogs, which exhibit a myriad of activities including MAO-A, DYRK1A and cytotoxicity to several select cancer cell lines.
RESULTS
Compounds 3e and 4c exhibited an IC of 0.83 ± 0.03 and 0.43 ± 0.002 μM against MAO-A and an IC of 0.26 ± 0.04 and 0.36 ± 0.001 μM against MAO-B, respectively. Molecular docking studies revealed π-π interactions between the synthesized molecules and aromatic amino acid residues. Conclusion & future perspective: The current study delineates the structural requirements for MAO-A selectivity and such information may be helpful in designing selective analogs for kinase, DYRK1A and harmine-based cytotoxics without apparent MAO enzyme inhibition.
Topics: Antineoplastic Agents; Click Chemistry; Harmine; Humans; Kinetics; Molecular Docking Simulation; Monoamine Oxidase; Monoamine Oxidase Inhibitors; Neoplasms; Protein Isoforms; Structure-Activity Relationship; Triazoles
PubMed: 29788780
DOI: 10.4155/fmc-2018-0006 -
The FEBS Journal Jun 2023Synthetic cannabinoid receptor agonists (SCRAs) are one of the fastest growing classes of recreational drugs. Despite their growth in use, their vast chemical diversity...
Synthetic cannabinoid receptor agonists (SCRAs) are one of the fastest growing classes of recreational drugs. Despite their growth in use, their vast chemical diversity and rapidly changing landscape of structures make understanding their effects challenging. In particular, the side effects for SCRA use are extremely diverse, but notably include severe outcomes such as cardiac arrest. These side effects appear at odds with the main putative mode of action, as full agonists of cannabinoid receptors. We have hypothesized that SCRAs may act as MAO inhibitors, owing to their structural similarity to known monoamine oxidase inhibitors (MAOI's) as well as matching clinical outcomes (hypertensive crisis) of 'monoaminergic toxicity' for users of MAOIs and some SCRA use. We have studied the potential for SCRA-mediated inhibition of MAO-A and MAO-B via a range of SCRAs used commonly in the UK, as well as structural analogues to prove the atomistic determinants of inhibition. By combining in silico and experimental kinetic studies we demonstrate that SCRAs are MAO-A-specific inhibitors and their affinity can vary significantly between SCRAs, most notably affected by the nature of the SCRA 'head' group. Our data allow us to posit a putative mechanism of inhibition. Crucially our data demonstrate that SCRA activity is not limited to just cannabinoid receptor agonism and that alternative interactions might account for some of the diversity of the observed side effects and that these effects can be SCRA-specific.
Topics: Cannabinoid Receptor Agonists; Kinetics; Illicit Drugs; Monoamine Oxidase Inhibitors; Monoamine Oxidase
PubMed: 36708234
DOI: 10.1111/febs.16741 -
Drug Design, Development and Therapy 2016Safinamide (SAF) is a new drug developed for the treatment of Parkinson's disease (PD). It is a benzylamino derivative with multiple mechanisms of action and... (Review)
Review
Safinamide (SAF) is a new drug developed for the treatment of Parkinson's disease (PD). It is a benzylamino derivative with multiple mechanisms of action and antiparkinsonian, anticonvulsant, and neuroprotective properties. SAF inhibits monoamine oxidase B and dopamine reuptake and glutamate release, blocks voltage-dependent sodium channels, and modulates calcium channels. Although the antiparkinsonian effect can be ascribed in part to the inhibition of the monoamine oxidase B, which is complete at 50 mg, the enhanced benefit seen at the 100 mg dose is probably due to nondopaminergic mechanisms. SAF will represent an important option for patients with both early and advanced PD. In early PD patients, the addition of SAF to dopamine agonists may be an effective treatment strategy to improve motor function, prolong the use of dopamine agonists, and/or delay the introduction of levodopa. In advanced parkinsonian patients, SAF has been demonstrated to significantly increase on time with no, or nontroublesome dyskinesias. All studies performed have demonstrated its efficacy in benefiting both short-term and long-term quality-of-life outcomes in both early and advanced PD patients. SAF has been investigated in long-term (24 months), double-blind, placebo-controlled studies, where it showed a very good safety profile. SAF has not been studied in de novo PD patients, and its potential positive effect on dyskinesia deserves further dedicated studies.
Topics: Adult; Aged; Alanine; Benzylamines; Double-Blind Method; Humans; Middle Aged; Monoamine Oxidase Inhibitors; Parkinson Disease; Randomized Controlled Trials as Topic
PubMed: 26917951
DOI: 10.2147/DDDT.S77749 -
The FEBS Journal Dec 2019The two human monoamine oxidase isoforms (namely MAO A and MAO B) are enzymes involved in the catabolism of monoamines, including neurotransmitters, and for this reason...
The two human monoamine oxidase isoforms (namely MAO A and MAO B) are enzymes involved in the catabolism of monoamines, including neurotransmitters, and for this reason are well-known and attractive pharmacological targets in neuropsychiatric and neurodegenerative diseases, for which novel pharmacological approaches are necessary. Benextramine is a tetraamine disulfide mainly known as irreversible α-adrenergic antagonist, but able to hit additional targets involved in neurodegeneration. As the molecular structures of monoamine oxidases contain nine cysteine residues, the aim of this study was to evaluate benextramine and eleven structurally related polyamine disulfides as potential MAO inhibitors. Most of the compounds were found to induce irreversible inactivation of MAOs with inactivation potency depending on both the polyamine structure and the enzyme isoform. The more effective compounds generally showed preference for MAO B. Structure-activity relationships studies revealed the key role played by the disulfide core of these molecules in the inactivation mechanism. Docking experiments pointed to Cys323, in MAO A, and Cys172, in MAO B, as target of this type of inhibitors thus suggesting that their covalent binding inside the MAO active site sterically impedes the entrance of substrate towards the FAD cofactor. The effectiveness of benextramine in inactivating MAOs was demonstrated in SH-SY5Y neuroblastoma cell line. These results demonstrated for the first time that benextramine and its derivatives can inactivate human MAOs exploiting a mechanism different from that of the classical MAO inhibitors and could be a starting point for the development of pharmacological tools in neurodegenerative diseases.
Topics: Cystamine; Enzyme Activation; Humans; Molecular Structure; Monoamine Oxidase; Monoamine Oxidase Inhibitors; Structure-Activity Relationship
PubMed: 31291696
DOI: 10.1111/febs.14994 -
British Journal of Pharmacology Jul 2016Alzheimer's disease (AD) is accepted nowadays as a complex neurodegenerative disorder with multifaceted cerebral pathologies, including extracellular deposition of... (Review)
Review
UNLABELLED
Alzheimer's disease (AD) is accepted nowadays as a complex neurodegenerative disorder with multifaceted cerebral pathologies, including extracellular deposition of amyloid β peptide-containing plaques, intracellular neurofibrillary tangles, progressive loss of cholinergic neurons, metal dyshomeostasis, mitochondrial dysfunction, neuroinflammation, glutamate excitoxicity, oxidative stress and increased MAO enzyme activity. This may explain why it is currently widely accepted that a more effective therapy for AD would result from the use of multifunctional drugs, which may affect more than one brain target involved in the disease pathology. The current review will discuss the potential benefits of novel multimodal neuroprotective, brain permeable drugs, recently developed by Youdim and collaborators, as a valuable therapeutic approach for AD treatment. The pharmacological and neuroprotective properties of these multitarget-directed ligands, which target MAO enzymes, the cholinergic system, iron accumulation and amyloid β peptide generation/aggregation are described, with a special emphasis on their potential therapeutic value for ageing and AD-associated cognitive functions. This review is conceived as a tribute to the broad neuropharmacology work of Professor Moussa Youdim, Professor Emeritus in the Faculty of Medicine and Director of Eve Topf Center of Excellence in Technion-Israel Institute of Technology, and Chief Scientific Officer of ABITAL Pharma Pipeline Ltd., at the occasion of his 75th birthday.
LINKED ARTICLES
This article is part of a themed section on Updating Neuropathology and Neuropharmacology of Monoaminergic Systems. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v173.13/issuetoc.
Topics: Aging; Alzheimer Disease; Amyloid beta-Peptides; Animals; Cholinesterase Inhibitors; Cholinesterases; Humans; Iron; Monoamine Oxidase; Monoamine Oxidase Inhibitors; Neuroprotective Agents
PubMed: 26332830
DOI: 10.1111/bph.13318