27 results on '"MONOAMINE oxidase"'
Search Results
2. Probing the active site of monoamine oxidase A with inhibitor ligands
- Author
-
Hynson, Robert Maurice George
- Subjects
QP603.M6H8 ,Monoamine oxidase ,Monoamine oxidase--Inhibitors ,Antidepressants--Mechanism of action - Published
- 2004
3. An investigation into the role and identity of tribulin
- Author
-
Doyle, Austin
- Subjects
612.014 ,Monoamine oxidase ,Benzodiazepine receptors - Published
- 1996
4. Molecular biology of X-chromosome disease
- Author
-
Chen, Zheng-Yi and Edwards, John Hilton
- Subjects
572.8 ,X chromosome ,Molecular aspects ,Abnormalities ,Genetic disorders ,Monoamine oxidase - Abstract
Genomic clones were isolated and characterized using the human monoamine oxidase A (MAOA) cDNA to screen a phage library, constructed from a human 4X cell line (48, XXXX). The genomic contig derived from overlapping phage clones showed that the size of the MAOA gene is over 80 kb. Exon-containing fragments from these phage clones were subcloned and sequenced. The data from this showed that the MAOA gene consists of 15 exons. A YAC (yeast artificial chromosome) isolated using the MAOA cDNA was characterized. This YAC was found to contain both the MAOA and the MAOB genes. Using PFGE (pulsed-field gel electrophoresis) to investigate the YAC, it was found that the MAOA and the MAOB genes are located within 50 kb and adjacent to each other. The two genes are localized in a 3'-to-3' fashion, suggesting their expression may be regulated independently. The analysis of the homology shown by the two genes clearly demonstrated that they were derived from duplication of a common ancestral gene. A CpG island was discovered to be associated with the 5' end of both genes. A restriction map of -2.5 Mb of genomic DMA around the MAO genes was generated by PFGE. Long-range mapping defined the physical relationship between the marker L1.28 and the MAO genes as L1.28_MAOA_MAOB. A number of genetic diseases have been linked to the Xp11.3 region. Strong linkage was known to exist between the Norrie disease locus and L1.28. Studies showed that some of the Norrie patients have deletions encompassing the region which contains L1.28 as well as the MAO genes. Another YAC isolated by using L1.28 as the probe was also characterized. A phage library was constructed from the L1.28 YAC and the end clones were isolated. Studies on some of the Norrie deletion patients showed that the proximal end clone of the YAC was retained in one of the deletion patients. Previous studies had shown that the Norrie disease locus was also localized proximal to the 5' end of the MAOB gene. The combined information placed the disease locus to an interval of 240 kb within the YAC. More phage clones were characterized in order to define further the region for the Norrie locus which was finally localized within 160 kb. A YAC fragment of 160 kb was isolated and used to screen two human retinal cDNA libraries. Among the cDNAs isolated, one group was found to be deleted in some of the Norrie patients previously without any known deletion, which established their candidacy as the transcripts of the Norrie disease locus. Further characterization of the candidate gene showed that it is conserved across species. The expression of the gene was detected in various tissues. The homology shared between the NDP gene and some of the growth factor binding proteins suggests its role in neural cell proliferation and differentiation.
- Published
- 1992
5. SYNTHESIS AND PHARMACOLOGY OF ILLUDALIC ACID AND ANALOGOUS CHEMICAL STRUCTURES
- Author
-
Gaston, Robert, Jr
- Subjects
- illudalane, sesquiterpene, fragmentation, monoamine oxidase, LAR, Vilsmeier- Haack, Wolff rearrangement, phosphatase, benzannulation, naphthalene, Medicinal-Pharmaceutical Chemistry, Organic Chemistry
- Abstract
Natural products are the foundation of modern medicine and an inspiration for chemical innovation. Developing new synthetic strategies to complex natural products drives synthetic innovation and promotes pharmacological exploration. As bioactive secondary metabolites of fungi, illudalic acid and associated analogs have unrealized medicinal potential due to synthetic limitations. Illudalic acid is notably the first selective covalent inhibitor of the LAR-PTPs, a class of enzymes linked to many human illnesses, including stimulant addiction. The chemistry herein focuses on optimizing synthetic routes to illudalic acid and associated analogs toward exploring their pharmaceutical potential. We report a second-generation synthesis of illudinine (55% overall yield), the alkaloid congener of illudalic acid, through the insertion of a small, linear nitrile. We also enhance our current 4-step illudalic acid synthesis via regioselective Vilsmeier- Haack formylation, taking advantage of bulky formamides. The high-yielding and regioselective Wolff rearrangement diazodimedone is another attractive way to assemble the illudalane core, but further exploration is needed to maximize it efficacy. Using an adapted benzannulation strategy, 25 illudalic acid analogs (illudalogs) containing a naphthalene core were prepared and screened against the LAR-PTP family. These are the most potent inhibitors reported to date, and coupled with their ease of synthesis (4-steps), make the illudalogs attractive chemotherapeutic scaffolds.
- Published
- 2023
6. Methamphetamine, Neurodegeneration, and Differential Vulnerability of Dopamine Neurons
- Author
-
Lee, You Bin
- Subjects
- methamphetamine, mitochondrial stress, monoamine oxidase, neurodegeneration, substantia nigra pars compacta, ventral tegmental area
- Abstract
Methamphetamine (meth) is an addictive and neurotoxic psychostimulant. Meth increases monoamine oxidase (MAO)-dependent axonal mitochondrial stress in substantia nigra pars compacta (SNc) dopamine (DA) neurons and chronic meth administration causes MAO-dependent SNc degeneration. Ventral tegmental area (VTA) neurons also express and utilize MAO to metabolize DA. The current study examined whether VTA neurons are vulnerable or resistant to chronic meth-induced degeneration and underlying mechanisms. We found that, similar to findings in SNc axons, meth induced MAO-dependent mitochondrial stress in VTA axons; however, the VTA was resistant to chronic meth-induced degeneration. The differentiating feature between SNc and VTA neurons was that SNc axons also had L-type Ca2+ channel (LCC)-dependent mitochondrial stress whereas VTA neurons did not. Both MAO and LCC inhibition attenuated meth-induced degeneration of SNc neurons as did a mitochondrial antioxidant. Together these data suggest that both MAO- and LCC-dependent mitochondrial stress are necessary for meth-induced degeneration.
- Published
- 2021
7. Novel properties of the multifaceted drug phenelzine and its metabolite β-phenylethylidenehydrazine
- Author
-
Matveychuk, Dmitriy
- Subjects
- Tyrosine, Amino acids, Neuroprotection, Reactive aldehydes, Monoamine oxidase, Phenelzine
- Abstract
Abstract: Phenelzine is a monoamine oxidase (MAO) inhibitor that has been used for the treatment of depression and anxiety disorders since the 1960s. In recent years, there has been renewed interest in this drug following reports of its neuroprotective properties in animal models of cerebral ischemia, multiple sclerosis and traumatic brain injury. It has been suggested that phenelzine is metabolized to an active metabolite, namely β-phenylethylidenehydrazine (PEH), by the action of MAO. PEH appears to share some of the neuroprotective properties of phenelzine and may be an interesting new drug in its own right. The work presented in this thesis has investigated the neurochemical effects of phenelzine and PEH and discussed these findings with regard to neuroprotection. First of all, the metabolism of phenelzine by human MAO-B was examined: this has included confirmation that PEH is a major product of phenelzine oxidation by the enzyme in vitro, studies examining the rate of PEH hydrolysis in aqueous media and elucidation of the mechanisms of MAO-B inhibition by phenelzine. Moreover, the effects of phenelzine and geometric isomers of PEH, (E)- and (Z)-PEH, on rat whole brain levels of amino acids, biogenic amine neurotransmitters and methylamine were compared. Both (E)- and (Z)-PEH appeared to be equivalent in their neurochemical properties under the conditions used in this study. Phenelzine and the PEH isomers produced marked increases in rat brain levels of γ-aminobutyric acid (GABA) and alanine while reducing levels of glutamine. Phenelzine, but neither PEH isomer, considerably elevated rat brain levels of serotonin, noradrenaline and dopamine. Rat brain levels of methylamine, a substrate for primary amine oxidase (PrAO), were elevated for all three drugs; however, the effect of phenelzine on methylamine was more transient in comparison to both PEH isomers. These findings provide support for the ability of phenelzine and PEH to inhibit PrAO, an enzyme that catalyzes the formation of toxic aldehydes and whose activity and expression have been reported to be increased in Alzheimer’s disease, in the rat brain. In addition, administration of both PEH isomers and phenelzine resulted in dramatic increases in rat whole brain tyrosine levels. It appears that the tyrosine-elevating property of phenelzine is mediated by PEH, as pre-treatment with another MAO inhibitor abolished the effect of phenelzine, but not of PEH, on brain tyrosine levels. Furthermore, phenelzine and PEH were effective at sequestering the toxic reactive aldehydes acrolein, malondialdehyde and methylglyoxal in vitro. In mouse cortical neurons, phenelzine and PEH attenuated acrolein-induced toxicity in a dose-dependent manner. However, neither phenelzine nor PEH reduced rat whole brain levels of extractable acrolein; phenelzine, but not PEH, reduced rat whole brain malondialdehyde levels. The findings presented in this thesis suggest that phenelzine and PEH possess several properties that may be relevant to neuroprotection. As such, they may prove to be useful adjunctive drugs in the treatment of numerous neurological disorders, such as cerebral ischemia, epilepsy, Alzheimer’s and Parkinson’s diseases. Further investigation of phenelzine and PEH with regard to application in these disorders is warranted.
- Published
- 2015
8. Characterisation of the imidazoline site on monoamine oxidase type B
- Author
-
McDonald, Glen Reid
- Subjects
- MAO-B, Phenylethylamine, 2-BFI, Enzyme kinetics, I2-site, Benzylamine, Monoamine oxidase, Imidazoline
- Abstract
Abstract: Monoamine oxidase enzymes are largely involved in the catabolism of biogenic amines. Two forms of the enzyme are socumented to exist, monoamine oxidase type A and B. The B form (MAO-B) of the enzyme has been noted to possess a high affinity site for some imidazoline ligands. This site (the I2 site) appears to exist only on a small fraction of MAO-B enzymes but the function of the site is not known. The ligands that bind to this site with high affinity appear to inhibit catalytic activity at concentrations some 1000-fold higher than those required to bind to the I2 site. The goal of the present work was to characterise the I2 site on MAO-B through radio-ligand binding and kinetic assays. In doing so, phenylethylamine was found to create a high-affinty site for 2-BFI on MAO-B. The rate of site-formation is influenced by the presence of 2-BFI. This work represents a new understanding of MAO-B kinetics and opens the door for future research into the potential importance of the I2 site on MAO-B.
- Published
- 2014
9. Inhibition of monoamine oxidase by derivatives of piperine, an alkaloid from the pepper plant Piper nigrum, for possible use in Parkinson’s disease
- Author
-
Al-Baghdadi, Osamah Basim Khalaf
- Subjects
- Pharmacology, Biomedical Research, Parkinsonism, Monoamine oxidase, High throughput screening, Drug design, structure-activity relationship study, Piperine, docking, Bovine serum albumin, Parkinson disease
- Abstract
Piperine has shown that it has wide range of effects, including monoamine oxidase B inhibitory effect which is one the targets in treating Parkinson disease. Piperine which is an alkaloid is the active ingredient of plant of black and white pepper grain, Piper nigrum. Several compounds related to piperine was screening using monoamine oxidase B and monoamine oxidase A assays. Z-factor statistical analysis showed that monoamine oxidase (A and B) assays was greater than (0.8). Most of test compounds were selective toward monoamine oxidase B enzyme, with the most potent compound with IC-50 of 498 micro molar . To obtain insight understanding of binding of test compounds to monoamine oxidase B enzyme, each test compound was docked to the crystal structure of monoamine oxidase B enzyme using Autodock 4.2 and Auto dock tools programs. Bovine serum albumin high throughput screening assay was performed to each test compound to understand their binding pattern to this carrier protein. To estimate blood brain barrier permeability, PAMPA method was used and it was showed that most test compounds be able to pass blood brain barrier. Taking together, the date obtained here may be useful in design selective monoamine oxidase B inhibitory compound without monoamine oxidase A activity that is able pass blood brain barrier and reach an active site.
- Published
- 2014
10. Identification of novel scaffolds for Monoamine oxidase B inhibitors
- Author
-
Odhar, Hasanain
- Subjects
- Biomedical Research, Neurosciences, Pharmaceuticals, Pharmacology, Pharmacy Sciences, Parkinsonism, Monoamine oxidase, Scaffold, High throughput screening, Drug design, structure-activity relationship study, Thiazolidine, 8-hydroxyquinoline, L-alanine
- Abstract
Parkinsonism is a progressive neurodegenerative disease that mainly affects elderly people. The disease is characterized by a progressive degeneration of dopaminergic neurons in the substantia nigra pars compacta region of the midbrain. This gradual loss of dopaminergic neurons will result in the appearance of four motor related symptoms and these are: tremor, bradykinesia, rigidity and postural imbalance. Current therapeutic approach focuses mainly on symptoms attenuation through dopamine replacement therapy. In this regard, recent drug design approaches are focused mainly on the production of multi targeted drug molecules as an attempt to generate a medication that is capable of halting or slowing down the progression of the degenerative process. Such goal can be achieved through the employment of designed multiple ligands (DMLs) strategy. MAO-B enzyme appears to be a promising target for such drug discovery approach. For our project, twenty four chemical compounds were selected (based on similarity analysis) as possible candidates for MAO-B inhibition. Structure-based virtual screening techniques (docking programs) were used to build an early impression about the binding tendency of these compounds to MAO-B crystal and bovine serum albumin (BSA) crystal. These compounds were then evaluated in vitro for their potentials to inhibit MAO isozymes and to quench peroxyl radicals. The pharmacokinetic profile for these compounds was investigated through the application of bovine serum albumin (BSA) binding assay and parallel artificial membrane permeability assay (PAMPA). Finally, a basic structure-activity relationship (SAR) study was established by comparing the structure, activity and docking images for compounds with related building blocks. As a conclusion to our SAR study, we believe that the 2-thioxo-1, 3-thiazolidin-4-one ring is essential for both MAO-B inhibition potential and radical quenching capacity. We also believe that 8-hydroxyquinoline moiety is essential for radical quenching activity; previous researches have shown that 8-hydroxyquinoline molecule can also act as a strong iron chelator. By combining 2-thioxo-1, 3-thiazolidin-4-one ring with 8-hydroxyquinoline moiety, we were able to generate two hypothetical scaffolds (scaffolds A and B). We believe that the attachment of L-alanine moiety to our design (scaffolds A and B) will enhance the selective delivery of these scaffolds into the brain. The addition of L-alanine will result in the generation of two additional scaffolds (E and F); these new scaffolds can act as good substrates to the large neutral amino acid transporter in the blood brain barrier. We believe that these scaffolds can be used for the development of a potent, selective and centrally acting MAO-B inhibitor with a possible radical quenching capacity and a promising iron chelating activity.
- Published
- 2014
11. Investigating Amine Oxidase Domain Containing Genes - amx-1 and amx-2 - in Caenorhabditis elegans
- Author
-
Basu, Reetobrata
- Subjects
- Animal Sciences, Behavioral Sciences, Biochemistry, Experiments, Genetics, Molecular Biology, Neurobiology, Neurology, Neurosciences, amx, Caenorhabditis elegans, monoamine oxidase, histone demethylase, monoamine, Reetobrata Basu, Janet Duerr, AMX, MAO, HDM, worm
- Abstract
Monoamine (MA) neurotransmitters affect multiple behaviors in animals. MA homeostasis is achieved partly by monoamine-oxidase (MAO) enzymes - a drug target for many human neuropsychiatric disorders. In C. elegans the MA pathway is similar to that in humans and the worm shows MA dependent behaviors, affected by MAO inhibitor (MAOI) treatments. We cloned, expressed and purified the C. elegans genes - amx-1 and amx-2 in heterologous systems. Absorption spectra indicated that AMX1 and AMX2 bind the redox cofactor flavin adenine dinucleotide (FAD). Biochemical assays with wild-type (N2) or mutant worm lysates showed significant differences in MAO and histone demethylase (HDM) activities between them. Purified AMX1 and AMX2 had very low in vitro HDM activity independently, but both significantly increased the HDM activity of worm lysates. AMX1 had negligible in vitro MAO activity, whereas AMX2 had high in vitro MAO activity, with substrate and inhibitor specificities.
- Published
- 2014
12. Novel neuroprotective compounds for use in Parkinson's disease
- Author
-
Shubbar, Ahmed
- Subjects
- Pharmacology, Biomedical Research, Neurosciences, Pharmacy Sciences, Pharmaceuticals, black pepper, natural product, high throughput screening, Monoamine oxidase, Parkinsonism
- Abstract
Parkinsonism is a neurodegenerative disease that mostly affects elderly people. Monoamine oxidase B (MAO-B) inhibitors have been used in the symptomatic treatment of motor symptoms of parkinsonism. Selective MAO-B inhibitors have also been shown to be neuroprotective agents. Using piperine, a natural alkaloid obtained from black pepper plant as lead compound, we initiated a virtual screen to identify novel selective MAO-B inhibitors. Twenty compounds were tested in several enzyme assays, with compounds 5223890 and 7691778 showing the most potent MAO-B inhibition. MAO-B IC50 for compounds 5223890 and 7691778 were found to be 286 nM and 599 nM, respectively. These compounds were also screened for antioxidant activity in the oxygen radical absorbance capacity (ORAC) assay and both of them have shown a mild to moderate antioxidant capacity which can increase their neuroprotective effects. Pharmacokinetic high-throughput studies using parallel artificial membrane permeability assay (PAMPA) and bovine serum albumin (BSA) binding assays indicated that these compounds will likely cross the blood-brain barrier and will moderately bind to serum albumin. Several studies have shown that the prevalence of mild cognitive impairment in patients with parkinsonism is about 30% .Interestingly, four of the tested compounds showed mild to moderate acetylcholinesterase inhibition activity .Compound F5123-0122 has shown the most potent inhibitory effect on acetylcholinesterase activity (AchE IC50 of 35.2 micro-Molar). These compounds may be useful for treating parkinsonism with comorbid mild cognitive impairment.
- Published
- 2013
13. Investigation of FAD Chemical Models to Study the Monoamine Oxidase Catalyzed Oxidation of Cyclic Tertiary-Allylamines
- Author
-
Nakamura, Akiko
- Subjects
- single electron transfer, FAD chemical model, monoamine oxidase, cyclic tertiary-allylamine, Parkinson's disease
- Abstract
Flavin adenine dinucleotide (FAD) is a coenzyme that participates in the redox process of flavoenzymes. Attempts to characterize the catalytic pathways of these enzymes have relied in part on the use of FAD chemical models. The efforts described in this dissertation focus on the chemical model approach to investigate the mechanism of the monoamine oxidase (MAO) catalyzed oxidation of the cyclic tertiary allylamine 1-methyl-4-(2-methyl-1H-pyrrol-2-yl)-1,2,3,6-tetrahydropyridine (TMMP), which is a close analog of the parkinsonian-inducing designer drug 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). MAO-B catalyzes the conversion of MPTP and its derivatives into active neurotoxins in the brain that subsequently mediate neurogenerative processes that mimic the events leading to idiopathic Parkinson\'s disease. Monoamine oxidase inhibitors are currently used to treat early stages of Parkinson\'s disease. Two FAD chemical models are examined in this project: 5-ethyl-3-methyllumiflavinium perchlorate (5Et3MLF+ClO4-) and 3-methyllumiflavin (3MLF). The flavinium salt 5Et3MLF+ClO4- is an activated form of 3MLF. These FAD chemical models have been used to examine the MAO catalyzed oxidation. MAO-B is expressed in the brain and is known to be involved in the conversion of TMMP into the neurotoxic metabolite 1-methyl-4-phenyl pyridnium (MMP+). MAO-B is responsible for the alpha-carbon oxidation of TMMP to yield 1-methyl-4-(2-methylpyrrol-2-yl)-2,3-dihydropyridinium (DHP+), which then undergoes a second 2-electron oxidation to MMP+. Previous findings demonstrated that 3MLF and 5Et3MLF+ClO4- promoted the oxidation reaction of primary and secondary amines but not tertiary amines. However, the cyclic tertiary allylamine TMMP has not been examined experimentally. Therefore, the alpha-carbon oxidation of TMMP in the presence of the FAD chemical models is reported in this dissertation. The effect of dioxygen and water on the activity of these FAD models is also investigated.
- Published
- 2013
14. The Antidepressant/Antipanic/Neuroprotective Drug Phenelzine: Neuropharmacological and Drug Metabolism Studies
- Author
-
Kumpula, David J
- Subjects
- Phenelzine, Phenylacetic acid, Alanine, Gamma-aminobutyric acid, Phenylethylamine, Phenylethylidenehydrazine, Monoamine oxidase inhibitors, Monoamine oxidase, Drug metabolism
- Abstract
Abstract: Phenelzine (PLZ) is a monoamine oxidase (MAO)-inhibiting antidepressant with anxiolytic and neuroprotective properties. Metabolites of PLZ were investigated in rat brain. Levels of phenylacetic acid (PAA) and β-phenylethylamine (PEA) were found to be elevated after administration of PLZ and PEH (a major metabolite of PLZ) to rats, but the effect was greater with PLZ in both cases. Acute administration of PLZ or PEH increased brain levels of alanine (ALA) and GABA and decreased glutamine (GLN) levels. When MAO was inhibited prior to PLZ administration, levels of GABA and ALA were not increased, supporting the idea that the metabolite PEH formed by MAO is responsible for the increases. Chronic PLZ administration significantly reduced weight gain in rats, and brain levels of amino acids were quite different after 1 and 3 weeks of PLZ administration, perhaps as a result of its decreased metabolism to PEH with time.
- Published
- 2013
15. Neurochemical and neuroprotective aspects of phenelzine and its active metabolite B-phenylethylidenehydrazine
- Author
-
MacKenzie, Erin Margaret
- Subjects
- Phenelzine, Formaldehyde, B-phenylethylidenehydrazine, GABA-transaminase, Semicarbazide-sensitive amine oxidase, Monoamine oxidase
- Abstract
Abstract: Phenelzine (PLZ) is a monoamine oxidase (MAO) inhibitor that also inhibits the activity of GABA-transaminase (GABA-T), causing significant and long-lasting increases in brain GABA levels. Inhibition of MAO prior to PLZ administration has been shown to prevent the GABAergic effects of the drug, strongly suggesting that a metabolite of PLZ formed by the action of MAO is responsible for the GABAergic effects. While PLZ has been used clinically for decades for its antidepressant and antipanic effects, it has more recently been shown to be neuroprotective in an animal model of ischemia. The aim of the experiments described in this thesis was to identify the active metabolite of PLZ, and to determine the neurochemical mechanisms by which PLZ and this metabolite exert their neuroprotective effects (with a particular focus on degenerative mechanisms observed in cerebral ischemia and Alzheimer’s disease (AD)). The development of an analytical assay for β-phenylethylidenehydrazine (PEH) was a major breakthrough in this project and permitted the positive identification of this compound as the active metabolite of PLZ. Further experiments demonstrated that PLZ and PEH could be neuroprotective in cerebral ischemia and AD not only by reducing excitotoxicity via increased GABAergic transmission, but also by (a) increasing brain ornithine, which could potentially lead to a decrease in glutamate synthesis and/or a decrease in polyamines (whose metabolism produces toxic aldehydes); (b) inhibiting the activity of human semicarbazide-sensitive amine oxidase (SSAO), an enzyme whose activity is increased in AD producing excessive amounts of the toxic aldehyde formaldehyde (FA); (c) by sequestering FA in vitro, forming a non-reactive hydrazone product. Since PEH appears to mediate or share the neurochemical effects of PLZ, two propargylated analogs of PEH were synthesized and tested for their potential as PEH prodrugs. Surprisingly these analogs were not particularly effective prodrugs in vivo, but they possessed an interesting neurochemical properties on their own (the ability to elevate brain levels of glycine), and warrant further investigation as potential antipsychotic agents. Together, these results suggest that PLZ and its active metabolite, PEH, should be further investigated for their neuroprotective potential in cerebral ischemia and in AD.
- Published
- 2009
16. Characterization of Three Putative Monoamine Oxidase Genes in Caenorhabditis elegans
- Author
-
Kaushal, Setu
- Subjects
- Biology, Cellular Biology, Molecular Biology, Caenorhabditis elegans, monoamines, monoamine oxidase, behavior, transgenics
- Abstract
Monoamine neurotransmitters like dopamine and serotonin regulate neuronal function and behavior in animals. In vertebrates, monoamine oxidase (MAO) degrades monoamines. We investigated the function of three amx genes, putative MAO genes in the nematode Caenorhabditis elegans. We hypothesized that if the amx genes encode MAOs, deletion mutants would have a partial or complete absence of MAO activity, causing an increase in monoamines levels, altered monoamine modulated behaviors and hypersensitivity to exogenous monoamines. Using glyoxylic acid induced fluorescence, we quantified dopamine and serotonin in the mutants but did not find any significant differences. However, the amx mutants exhibited abnormalities in some monoamine modulated behaviors and increased sensitivity to exogenous dopamine and serotonin. Finally and interestingly, we found that Pamx-1::GFP transgenic lines suggested that amx-1 was expressed predominantly in chemosensory neurons.
- Published
- 2008
17. Monoamine Oxidase and Sensory Gating: Psychophysiological Vulnerabilities among Teenage Smokers
- Author
-
Wan, Li
- Subjects
- Sensory Gating, Monoamine Oxidase, Psychophysiological Vulnerabilities, Neurotransmitters, Teenage Smoking
- Abstract
Smoking is one of the leading causes of death in the world. About 80% of smokers start smoking before the age of 18. In the Appalachian area and the South in the United States, smoking percentages among adults and adolescents are higher than in other regions. Female smoking shows a variety of different trends from male smoking, and smoking brings particular health problems related to production to female smokers. These findings highlighted the importance of studying female teenage smokers in southwest Virginia. The initial project aimed to identify risk factors that might prevent smoking in an early stage. Dr. Helen Crawford led the Cognitive Neuroscience Lab at Virginia Tech in discovering the psychophysiological vulnerabilities of female teenage smokers. Toward this end, event-related potential (ERP), personality, and behavioral data were collected in teenage female smokers and non-smokers. These data were analyzed to examine possible psychophysiological vulnerabilities in female teenage smokers such as deficits in brain and cognitive function, personality traits, and environment influences. The purpose of this dissertation is to further analyze these data to elaborate and clarify the relationships among these vulnerabilities toward understanding teenage smoking behavior. Participants were 49 teenage girls (smokers and non-smokers) with age from 14 to 18. The measures included sensory gating, platelet MAO-B activity, attention, memory, temperament, schizotypal personality, recognition of facial expressions, taste and smell. The initial set of analyses compared smokers and non-smokers, including those classified as high and low dependent, on all dependent measures. The results suggested some psychophysiological vulnerabilities in female teenage smokers, which have been used as support for the self-medication and the orbito-frontal dysfunction models of why teenagers smoke (Crawford et al., 2004). Further examination of these factors may help teenagers to reduce the smoking dependency and possibly improve cognitive function. Specifically, this dissertation focused on the role of the variable of monoamine oxidase-B (MAO-B) in the correlations among sensory gating, MAO and other cognitive and personality measures. All smokers were divided into high and low MAO groups first. Comparison analyses were conducted between them. The high MAO group showed better sensory gating function than the low MAO group. Correlation analyses were conducted among all of the measures. The significant linear relationships between MAO and sensory gating, MAO and CO level and MAO and temperament were demonstrated. MAO activity positively correlated with the sensory gating function and negatively correlated with CO level and temperament characteristics. Finally, to explore the mechanisms of the relationship between MAO and sensory gating, the neurotransmitter systems related to MAO and sensory gating were discussed.
- Published
- 2006
18. Studies on the Synthesis and Rearrangement of Indazolylpyridinium Derivatives Precursors to Potential Neuroprotective Prodrugs Bearing a 1,2,3,6-Tetrahydropyridinyl Carrier
- Author
-
Isin, Emre Mehmet
- Subjects
- Regiospecific synthesis, Monoamine oxidase, Bioactivation, Docking, Neuroprotection, Rearrangement
- Abstract
The neuronal nitric oxide synthase (nNOS) inhibitor 7-nitroindazole (7-NI) protects against the neurotoxicity of MPTP in a mouse model of neurodegeneration. Since 7-NI also inhibits the monoamine oxidase-B (MAO-B) catalyzed bioactivation of MPTP, the role of nNOS inhibition as a mediator of 7-NI's neuroprotective properties have been challenged. In order to examine in greater detail the neuroprotective effects of indazolyl derivatives, the synthesis of water soluble indazolyltetrahydropyridinyl derivatives as potential "prodrugs" that may undergo MAO bioactivation in the brain was undertaken. During the course of the studies on the synthesis of indazolylpyridinium derivatives, precursors to these "prodrugs", an interesting reaction involving the rearrangement of 4-(2H-indazolyl)-1-methylpyridinium iodide to the corresponding 1H-isomer was encountered. A detailed investigation of this rearrangement reaction is reported in this thesis. The syntheses and interaction of nitroindazolyltetrahydropyridinyl "prodrugs" with MAO-B have been investigated previously. Molecular docking studies that attempt to explain the MAO-B substrate and inhibitor properties of members of this series of compounds are described. Finally, the MAO-A substrate properties of nitroindazolyltetrahydropyridinyl derivatives are reported.
- Published
- 2004
19. Studies on the monoamine oxidase substrate/inactivator properties of piperidine analogs of the neurotoxin MPTP
- Author
-
Chi, Feng
- Subjects
- piperidine, MPTP, monoamine oxidase, mechanism, bioactivity
- Abstract
The unexpected monoamine oxidase (MAO) substrate properties of 1-cyclopropyl-4-substituted-1 ,2,3,6-tetrahydropyridines have been interpreted in terms of partitioning of these tertiary cyclic allylamines between substrate turnover and ring opening inactivation processes. To evaluate further this proposal, we examined the bioactivities of the related saturated analogs. Several 1,4-disubstituted piperidine derivatives were synthesized and their interactions with MAO-A and MAO-B were characterized. These compounds displayed poor substrate properties toward MAO-A and MAO-B and led to the expected α-carbon oxidized metabolites which were fully characterized. Both the N-methyl and N-cyclopropyl derivatives were good inactivators of MAO-B, suggesting that some species other than the radical resulting from cyclopropyl ring opening is responsible for the inactivation. Both the N-methyl and N-cyclopropyl derivatives also inactivated MAO-A. In this instance, the N-cyclopropyl analogs were much more potent inactivators than the N-methyl analogs. These results suggest that the radical derived from cyclopropyl ring opening may be involved in this inactivation process. The MAO substrate/inactivator properties of these piperidine analogs are discussed in terms of current proposed mechanisms for the MAO catalyzed oxidation of amines.
- Published
- 1996
20. Hyperbaric reversal of methohexital-induced alterations of monoamine oxidase inhibition /
- Author
-
Glenn, James Donald
- Subjects
- Health Sciences, Monoamine oxidase
- Published
- 1977
21. Mechanistic Studies on the Monoamine Oxidase B Catalyzed Oxidation of 1,4-Disubstituted Tetrahydropyridine Derivatives
- Author
-
Anderson, Andrea H.
- Subjects
- single electron transfer, hydrogen atom transfer, monoamine oxidase
- Abstract
The flavin-containing monoamine oxidases (MAO) A and B catalyze the oxidative deamination of primary and secondary amines. The overall process involves a two electron oxidation of the amine to the iminium with concomitantreduction of the flavin. Based on extensive studies with a variety of chemical probes, Silverman and colleagues have proposed a catalytic pathway for the processing of amine substrates and inactivators by MAO-B that is initiated by a single electron transfer (SET) step from the nitrogen lone pair to the oxidized flavin followed by α-proton loss from the resulting amine radical cation that leads to a carbon radical. Subsequent transfer of the second electron leads to the reduced flavin and the iminium product. In the case of N-cyclopropylamines, the initially formed amine radical cation is proposed to undergo rapid ring opening to form a highly reactive primary carbon centered radical that is thought to be responsible for inactivation of the enzyme. In this thesis we have exploited the unique substrate and inactivator properties of 1,4-disubstituted tetrahydropyridine derivatives to probe the mechanism of MAO-B catalysis. Reports of the parkinsonian inducing neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) as a structurally unique substrate of MAO-B initiated these studies. Consistent with the SET pathway, the N-cyclopropyl analog of MPTP proved to be an efficient time and concentration dependent inactivator but not a substrate of MAO-B. On the other hand, the 4-benzyl-1-cyclopropyl analog is both a substrate and inactivator of MAO-B. These properties may not be consistent with the obligatory formation of a cyclopropylaminyl radicalcation intermediate. In an attempt to gain further insight into the mechanism associated with the MAO catalyzed oxidation of 1,4-disubstituted tetrahydropyridines, deuterium isotope effects studies on both the substrate and inactivation properties of the 4-benzyl-1- cyclopropyl derivative were undertaken. A series of 1-methyl- and 1-cyclopropyltetrahydropyridine derivatives bearing various heteroaro-matic groups at C-4 also have been examined. The MAO-B substrate properties, inactivator properties and partition ratios for these compounds together with preliminary results from chemical model studies are discussed in terms of the MAO-B catalytic pathway.
- Published
- 1997
22. The Investigation of the Active Sites of Monoamine Oxidase (MAO) A and B and the Study of MAO-A Mediated Neurotoxicity Using 4-Substituted Tetrahydropyridines
- Author
-
Palmer, Sonya Lenette Jr.
- Subjects
- Monoamine Oxidase, Active Sites, Neurotoxicity, Enzymology
- Abstract
The mitochondrial membrane bound flavoenzymes monoamine oxidase A and B (MAO-A and MAO-B) catalyze the a-carbon oxidation of a variety of amines including neurotransmitters such as dopamine and serotonin. Although the primary structures of these enzymes have been established from the corresponding gene sequences, relatively little is known regarding the structural features of the active sites which lead to the selectivities observed with various substrates and inhibitors. In spite of many efforts, these enzymes have not been crystallized. In the absence of X-ray structures, the design, synthesis, and evaluation of biological activity remain the only way to assess a view of the active sites, through SAR and QSAR studies. The excellent MAO-A and/or B substrate and inhibitor properties of various 1,4-disubstituted-1,2,3,6-tetrahydropyridine derivatives offer an interesting opportunity to probe the active sites of MAO-A and MAO-B. In an effort to explore the spatial features of the active sites, we have synthesized series of substituted tetrahydropyridines, evaluated their biological activity with purified MAO-A and MAO-B, and carried out a topological analysis of the MAO active sites using molecular modeling. In addition, the results described in this thesis provide evidence that the MAO-A and MAO-B active sites differ in shape, regions of activity, and areas that tolerate polar interactions. The role of MAO in neurodegenerative processes such as Parkinson's Disease has been recognized for some time. The structurally unique parkinsonian inducing substrate 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) is bioactivated to neurotoxic metabolites. The mechanism of neurotoxicity has been studied extensively and it is known that MAO-B catalyzes the conversion of MPTP to the 2,3-dihydro-1-methyl-4-phenylpyridinium species (MPDP+) which undergoes further oxidation to the neurotoxic metabolite 1-methyl-4-phenyl pyridnium (MPP+). However, the role of MAO-A in mediating a neurotoxic response, has not been fully defined due to the lack of selective MAO-A substrates. In this thesis, we have investigated the neurotoxic potential of several tetrahydropyridines in C57Bl/6 mice and the ability of selective inhibitors to protect against the expression of MAO mediated neurotoxicity.
- Published
- 1998
23. Synthesis and mechanistic studies on the monoamine oxidase (MAO) catalyzed oxidation of 1,4-disubstituted-1,2,3,6-tetrahydropyridines
- Author
-
Yu, Jian
- Subjects
- monoamine oxidase, tetrahydropyridine, isotope effect, deuterium, chiral auxiliary
- Abstract
The parkinsonian inducing drug 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) is bioactivated in a reaction catalyzed by the flavoenzyme monoamine oxidase B (MAO-B) to form the corresponding dihydropyridinium (MPDP+) subsequently pyridinium (MPP+) metabolites. As part of our ongoing studies to characterize the structural features responsible for this unexpected biotransformation, we have synthesized and examined the MAO-B substrate properties of a variety of MPTP analogs bearing various heteroaryl groups at the 4-position of the tetrahydropyridinyl ring. The results of these SAR studies indicate that electronic features, steric features and polar interactions can contribute to the substrate activities. Additionally, isotope effects have been examined to investigate the mechanism and stereoselectivity of the MAO-B catalytic pathway. The synthesis and characterization of regio and stereoselectively deuterated MPTP analogs have been achieved. The results indicate that the catalytic step occurs exclusively at the allylic C-6 position and is rate-determining for both good and poor substrates. The two enantiomers of MPTP bearing a deuterium atom at C-6 have been prepared via chiral aminooxazolinyl derivatives and have been characterized by 2H NMR in a chiral liquid crystal matrix. These enantiomers were used to determine the selectivity of the MAO-B catalyzed a C-H bond cleavage reaction leading to the dihydropyridinium metabolite MPDP+. Some of the cyclopropyl analogs of MPTP have also been synthesized as the potential inhibitors.
- Published
- 1998
24. Psychometric and biochemical indices of psychiatric vulnerability : electrophysiological and psychological correlates
- Author
-
Ward, Philip Bentley
- Subjects
- Mental illness, Monoamine oxidase, Psychometrics, Evoked potentials (Electrophysiology)
- Published
- 1988
25. Central neural regulation of glucose and insulin
- Author
-
Grunstein, Harry Sidney
- Subjects
- Blood sugar, Monoamine oxidase, Insulin, Hypothalamus, Homeostasis
- Published
- 1985
26. Synthesis and biological activity of analogs of the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydrophyridine (MPTP) and its monoamine oxidase derived metabolites
- Author
-
Johnson, Elizabeth Anne
- Subjects
- Methylphenyltetrahydropyridine, Monoamine oxidase, Structure-activity relationships (Biochemistry)
- Published
- 1989
27. Mechanistic studies on the monoamine oxidase B catalyzed oxidation of the neurotoxin 1-methyl-4-phenyl-1,2,3,6- tetrahydropyridine (MPTP)
- Author
-
Ottoboni, Susanne,
- Subjects
- Methylphenyltetrahydropyridine, Monoamine oxidase
- Published
- 1989
Catalog
Discovery Service for Jio Institute Digital Library
For full access to our library's resources, please sign in.