Showing papers on "Monoamine oxidase B published in 2005"

Sertraline is metabolized by multiple cytochrome p450 enzymes, monoamine oxidases, and glucuronyl transferases in human: an in vitro study

Abstract: The oxidative and conjugative metabolism of sertraline was examined in vitro to identify the enzymes involved in the generation of N -desmethyl, deaminated, and N -carbamoyl-glucuronidated metabolites in humans. In human liver microsomes, sertraline was N -demethylated and deaminated by cytochrome P450 (P450) enzymes with overall K m values of 98 and 114 μM, respectively, but the intrinsic clearance for N -demethylation was approximately 20-fold greater than for deamination. Using P450 isoform-selective inhibitors and recombinant heterologously expressed enzymes, it was demonstrated that several P450 enzymes catalyzed sertraline N -demethylation, with CYP2B6 contributing the greatest extent, and lesser contributions from CYP2C19, CYP2C9, CYP3A4, and CYP2D6. For deamination, data supported a role for CYP3A4 and CYP2C19. Purified human monoamine oxidases A and B also catalyzed sertraline deamination with comparable K m values (230-270 μM). Monoamine oxidase B catalyzed the reaction approximately 3-fold faster than did monoamine oxidase A. Sertraline N -carbamoyl glucuronidation was measured in human liver microsomes in bicarbonate buffer and under a CO 2 atmosphere ( K m = 50 μM) and was catalyzed at the fastest rate by recombinant human UGT2B7. The observation that multiple enzymes appear to be involved in sertraline metabolism suggests that there should be no single agent that could substantially alter the pharmacokinetics of sertraline, nor should there be any single drug-metabolizing enzyme genetic polymorphism (e.g., CYP2D6, CYP2C19, CYP2C9, UGT1A1) that could profoundly impact the pharmacokinetics of sertraline.

Structure and Mechanism of Monoamine Oxidase

Abstract: Monoamine oxidases A and B (MAO A and MAO B) are mitochondrial outer membrane-bound flavoproteins that catalyze the oxidative deamination of neurotransmitters and biogenic amines. A number of mechanism-based inhibitors (MAOIs) have been developed for clinical use as antidepressants and as neuroprotective drugs. To facilitate the development of more effective and specific inhibitors, a detailed understanding of the structures and catalytic mechanisms of these enzymes is required. The recent development of high level expression systems for producing recombinant human liver MAO A and MAO B in Pichia pastoris has facilitated the determination of the three-dimensional crystal structures of MAO B (up to 1.7 A resolution) in complex with different reversible (isatin, 1,4-diphenyl-2-butene) and irreversible inhibitors (pargyline, N-(2-aminoethyl)-p-chlorobenzamide, and trans-2-phenylcyclopropylamine). The binding of substrates or inhibitors to MAO B involves an initial negotiation of a protein loop occurring near the surface of the membrane and two hydrophobic cavities; an “entrance” cavity and an “active site” cavity. These two cavities can either be separate or in a fused state depending on the conformation of the Ile199 side chain, which appears to function as a gate. The amine function of the bound substrate approaches the re face of the bent and “puckered” covalent FAD through an “aromatic cage” formed by two tyrosine residues that are perpendicular to the plane of the flavin ring. No amino acid residues that could function as acids or bases are found near the catalytic site. The existing structural data on MAO B support previous QSAR results and are also supportive of a proposed polar nucleophilic mechanism for MAO A and B catalysis rather than the alternatively proposed single electron transfer (SET) mechanism. Keywords: Monoamine oxidase A (MAO A); Monoamine oxidase B (MAO B); Catalytic mechanisms; Three-dimensional structure

Sulfur-Substituted α-Alkyl Phenethylamines as Selective and Reversible MAO-A Inhibitors: Biological Activities, CoMFA Analysis, and Active Site Modeling

Abstract: A series of phenethylamine derivatives with various ring substituents and with or without N-methyl and/or C-α methyl or ethyl groups was synthesized and assayed for their ability reversibly to inhibit monoamine oxidase A (MAO-A) and monoamine oxidase B (MAO-B). Several compounds showed potent and selective MAO-A inhibitory activity (IC50 in the submicromolar range) but none showed appreciable activity toward MAO-B. A three-dimensional quantitative structure−activity relationship study for MAO-A inhibition was performed on the series using comparative molecular field analysis (CoMFA). The resulting model gave a cross-validated q2 of 0.72 and showed that in this series of compounds steric properties of the substituents were more important than electrostatic effects. Molecular modeling based on the recently published crystal structure of inhibitor-bound MAO-A provided detailed evidence for specific interactions of the ligands with the enzyme, supported by previous references and consistent with results from ...

Translational Neuroimaging: Positron Emission Tomography Studies of Monoamine Oxidase

Abstract: Positron emission tomography (PET) using radiotracers with high molecular specificity is an important scientific tool in studies of monoamine oxidase (MAO), an important enzyme in the regulation of the neurotransmitters dopamine, norepinephrine, and serotonin as well as the dietary amine, tyramine. MAO occurs in two different subtypes, MAO A and MAO B, which have different substrate and inhibitor specificity and which are different gene products. The highly variable subtype distribution with different species makes human studies of special value. MAO A and B can be imaged in the human brain and certain peripheral organs using PET and carbon-11 (half-life 20.4 minutes) labeled mechanism-based irreversible inhibitors, clorgyline and l-deprenyl, respectively. In this article we introduce MAO and describe the development of these radiotracers and their translation from preclinical studies to the investigation of variables affecting MAO in the human brain and peripheral organs.

In Vivo Measurement of Brain Monoamine Oxidase B Occupancy by Rasagiline, Using 11C-l-Deprenyl and PET

Abstract: In recent years, monoamine oxidase B (MAO-B) inhibitors have become widely used in the treatment of early-stage Parkinson’s disease 11C-l-deprenyl PET has been used by others to characterize MAO-B ligands in terms of their in vivo potency toward MAO-B and duration of action In this study, we used 11C-l-deprenyl PET to demonstrate the specific binding characteristics of the new irreversible selective MAO-B inhibitor rasagiline in 3 healthy volunteers Methods: The healthy volunteers received 1 mg of rasagiline daily for 10 d Dynamic 11C-l-deprenyl PET brain scans were acquired before the first treatment (scan 1) and immediately (scan 2), 2–3 wk (scan 3), and 4–6 wk (scan 4) after the final treatment Results: On scan 1, all subjects showed the highest l-deprenyl uptake in the thalamus and basal ganglia, with fairly high activity also in the cortex and cerebellum and much lower activity in the white matter The areas of high uptake were absent from scan 2, on which activity throughout the brain was comparable to that in white matter, presumably because of blocking of MAO-B binding sites by rasagiline Gradual recovery toward the baseline state was observed in the weeks after termination of treatment (scans 3 and 4) Conclusion:11C-l-deprenyl PET showed binding of rasagiline to MAO-B, confirming blocking of MAO-B sites after 10 d of treatment with 1 mg of rasagiline per day, with immediate post-rasagiline treatment tracer uptake and metabolism in the basal ganglia compatible only with nonspecific binding Subsequent gradual recovery was also seen, with return to near-baseline uptake This finding is compatible with the known rate of de novo synthesis of MAO-B, confirming the irreversible binding of rasagiline

Design, synthesis, and biological activities of pyrrolylethanoneamine derivatives, a novel class of monoamine oxidases inhibitors.

Abstract: Pyrrolylethanoneamines 1-12, 18-23 and related amino alcohols 13-15, 24-27 were synthesized and tested against monoamine oxidases A and B (MAO-A and MAO-B) enzymes. In general, aminoketones 1-12, 18-23 were found to be potent and selective MAO-A inhibitors. In particular, 18 was more potent and selective against the MAO-A isoenzyme than reference drugs. Interestingly, amino alcohol 25 selectively inhibited MAO-B enzyme and could be a lead compound for designing more potent and selective MAO-B inhibitors.

Association study of a functional MAOA-uVNTR gene polymorphism and personality traits in Chinese young females.

Abstract: Monoamine oxidase A (MAOA), a mitochondrial outer membrane enzyme, degrades biogenic amines including norepinephrine, dopamine and serotonin, which have been implicated in the expression of personality traits. We tested the associations between functional MAOA-uVNTR genetic variants and personality traits in a cohort of 370 healthy young Chinese females. Subjects who were homozygous for the 4-repeat allele of the MAOA-uVNTR gene tended to have a higher total score on the Harm Avoidance (HA) dimension of the Tridimensional Personality Questionnaire (TPQ) (p = 0.056), and had a significantly higher score on subdimension 4 of HA (p = 0.020) compared with the 3-repeat carriers. No significant association was demonstrated for MAOA-uVNTR polymorphism and the other two dimensions (Novelty Seeking and Reward Dependence) of TPQ. These results suggest that genetic variants of the MAOA gene may play a role in HA, but not in Novelty Seeking or Reward Dependence.

Neuroprotective effect of rasagiline, a monoamine oxidase-B inhibitor, on spontaneous cell degeneration in a rat model.

Abstract: Spontaneously hypertensive rats (SHR) pathologically elevate blood pressure with age. This elevation is accompanied by specific neuronal degeneration in the hypothalamus and enlargement of the lateral ventricles. The aim of this study was to assess the neuroprotective effect of the monoamine oxidase B (MAO-B) inhibitor, rasagiline on paraventricular (PVN) hypothalamic degeneration in SHR. The S-enantiomer of rasagiline, S-PAI, a much weaker MAO inhibitor, and two antihypertensive drugs, captopril and hydralazine were also tested. Normotensive Wistar Kyoto (WKY) rats served as controls. One month-old SHR or WKY rats were treated daily for 3-4 months. Systolic blood pressure was recorded, parvocellular vasopressin (VP) immunopositive cells were counted and the area of the third ventricle measured. In saline-treated SHR, blood pressure rose significantly and the number of VP parvocellular cells was reduced by about 60% relative to WKY. Rasagiline, 1 mg/kg/day, reduced PVN neuronal cell death in SHR up to 112% relative to saline-treated SHR; 0.3 mg/kg/day exerted a smaller but significant effect. These actions were accompanied by parallel reductions in systolic blood pressure. Captoril, hydralazine and S-PAI did not prevent death of VP neurons. In SHR, the volume of the third ventricle was about double that of WKY. Rasagiline significantly prevented this ventricular dilation. These results indicate than rasagiline protects from cell death in an in vivo animal model in a dose-dependant manner and could be of use as a neuroprotector in the central nervous system.

Stereospecific oxidation of the (S)-enantiomer of RS-8359, a selective and reversible monoamine oxidase A (MAO-A) inhibitor, by aldehyde oxidase.

Abstract: In a previous paper by the authors on RS-8359, a new selective and reversible monoamine oxidase A (MAO-A) inhibitor, it was reported that the (S)-enantiomer of RS-8359 is rapidly eliminated from rats, monkeys and humans as a result of the formation of a 2-oxidative metabolite. The present study investigates the properties of the enzyme responsible for the 2-oxidation of RS-8359. Subcellular localization, cofactor requirement and the inhibitory effects of typical compounds were studied using rat liver preparations. In addition, the enzyme was purified from rat liver cytosol for further characterization. The enzyme activity was localized in the cytosolic fraction without the need for any cofactor and was extensively inhibited by menadione, chlorpromazine and quinacrine. The purified enzyme was also a homodimer with a monomeric molecular weight of 140 kDa and it had an A280/A450 ratio of 5.1 in the absorption spectrum. The results suggest that the enzyme responsible for the biotransformation of RS-8359 to give the 2-keto derivative is aldehyde oxidase (EC 1.2.3.1). The reaction of aldehyde oxidase is highly stereoselective for the (S)-configuration of RS-8359 and the (9R)-configuration of cinchona alkaloids.

Catechol-O-Methyltransferase and Monoamine Oxidase B Genes and Susceptibility to Sporadic Parkinson’s Disease in a Polish Population

Abstract: Recent reports have proved that genetic factors play a role in the pathogenesis of sporadic Parkinson’s disease (PD). It has been suggested that polymorphisms in monoamine oxidase B (MAOB) and catecho

Development of fluorogenic substrates for monoamine oxidases (mao-a and mao-b)

Abstract: The present invention relates to compounds useful for detecting the activity of monoamine oxidases, compounds useful for competitively inhibiting monoamine oxidases, for determining inhibitors of monoamine oxidases and compounds useful for treating monoamine oxidase-related nervous system pathologies, as well as pharmaceutical compositions and methods of manufacture thereof.

Identification of an cysteine-to-arginine substitution caused by a single nucleotide polymorphism in the canine monoamine oxidase B gene.

Abstract: Monoamine oxidase B catalytically oxidizes biogenic amines such as phenylethylamine and dopamine, and its activity is presumed to be related to particular behavioral traits. In this study, we first identified a single nucleotide polymorphism (T199C) located on the putative third exon of the canine monoamine oxidase B gene, which causes an amino acid substitution from cysteine to arginine. We then examined the allelic frequencies in five dog breeds (Golden Retriever, Labrador Retriever, Maltese, Miniature Schnauzer, and Shiba) and found significant variation among them. The present results suggest that analysis of the monoamine oxidase B polymorphism could be a useful means of elucidating the genetic background of breed-specific behavioral characteristics in dogs.

Effect of some isoquinoline alkaloids on enzymatic activity of acetylcholinesterase and monoamine oxidase

Abstract: It has been shown, that some benzo[c]-phenanthridine and diisoquinoline alkaloids isolated from Chelidonium majus L and Macleaya (Bocconia) cordata and M microcarpa (berberine, sanguinarine, chelidonine) and of drugs ("Ukrain" and "Sanguirythrine") inhibited the enzyme activity of acetylcholinesterase from human erythrocyte and monoamine oxidase from the rat liver All agents under study have been shown to be reversible inhibitors of the enzymatic hydrolysis of acetylthiocholine It has been determined that chelidonine belonged to reversible inhibitors of a competitive type, all other examined agents have been demonstrated to be inhibitors of a mixed competitive-noncompetitive type, and a greater contribution to the inhibition was made by the competitive constituent Among all examined agents berberine, sanguinarine and "Sanguirythrine" were the strongest inhibitors of this reaction and chelidonine and "Ukrain" were much weaker All agents under study have been shown to be irreversible inhibitors of the oxidative deamination reaction of serotonine and tyramine and not to influence the oxidative deamination reaction of benzylamine as a substrate Among the examined agents, alkaloid sanguinarine and drug "Ukrain" are the strongest inhibitors of the reaction, alkaloids berberine, sanguinarine and "Sanguirythrine" exhibit a weaker action

Inhibitory Effect of Silkworm-Extract(SE) on Monoamine Oxidase Activity in Vitro and in Vivo

Abstract: In vitro.MAO-A activity was inhibited 16-25%, and MAO-B activity was inhibited 20-50% by SE treatment (12.5, 25 and 50 μg), In vivo.male C57BL/6 mice Received intraperitoneal injection of SE (20 mg/kg/day) for 14 days. The results showed that MAO-A activity of pre-SE-treatment mice brain was inhibited in whole brain, cerebral cortex, substantia nigra. MAO-B activity of pre-SE-treatment mice brain was inhibited in substantia nigra and cerebellum than saline-treated control group. These results suggest that SE inhibits MAO activity in vivo.which would be expected to results in anti-depressive and neuroprotective effects.

Immunohistochemical Localization of Monoamine Oxidase Type B in Pancreatic Islets of the Rat

Abstract: Monoamine oxidase (MAO) is regarded as a mitochondrial enzyme. This enzyme localizes on the outer membrane of mitochondria. There are two kinds of MAO isozymes, MAO type A (MAOA) and type B (MAOB). Previous studies have shown that MAOB activity is found in the pancreatic islets. This activity in the islets is increased by the fasting-induced decrease of plasma glucose level. Islet B cells contain monoamines in their secretory granules. These monoamines inhibit the secretion of insulin from the B cells. MAOB is active in degrading monoamines. Therefore, MAOB may influence the insulin-secretory process by regulating the stores of monoamines in the B cells. However, it has not been determined whether MAOB is localized on B cells or other cell types of the islets. In the present study, we used both double-labeling immunofluorescence histochemical and electron microscopic immunohistochemical methods to examine the subcellular localization of MAOB in rat pancreatic islets. MAOB was found in the mitochondrial outer membranes of glucagon-secreting cells (A cells), insulin-secreting cells (B cells), and some pancreatic polypeptide (PP)-secreting cells (PP cells), but no MAOB was found in somatostatin-secreting cells (D cells), nor in certain other PP cells. There were two kinds of mitochondria in pancreatic islet B cells: one contains MAOB on their outer membranes, but a substantial proportion of them lack this enzyme. Our findings indicate that pancreatic islet B cells contain MAOB on their mitochondrial outer membranes, and this enzyme may be involved in the regulation of monoamine levels and insulin secretion in the B cells.