Showing papers on "Monoamine oxidase B published in 2006"
TL;DR: The concept of neuroprotection, reflecting the possibility of slowing, halting and maybe reversing, neurodegeneration in Parkinson's or Alzheimer's diseases, and selective inhibition of brain MAO could contribute importantly to lowering such stress are suggested.
Abstract: A few years after the foundation of the British Pharmacological Society, monoamine oxidase (MAO) was recognized as an enzyme of crucial interest to pharmacologists because it catalyzed the major inactivation pathway for the catecholamine neurotransmitters, noradrenaline, adrenaline and dopamine (and, later, 5-hydroxytryptamine, as well). Within the next decade, the therapeutic value of inhibitors of MAO in the treatment of depressive illness was established. Although this first clinical use exposed serious side effects, pharmacological interest in, and investigation of, MAO continued, resulting in the characterization of two isoforms, MAO-A and -B, and isoform-selective inhibitors. Selective inhibitors of MAO-B have found a therapeutic role in the treatment of Parkinson's disease and further developments have provided reversible inhibitors of MAO-A, which offer antidepressant activity without the serious side effects of the earlier inhibitors. Clinical observation and subsequent pharmacological analysis have also generated the concept of neuroprotection, reflecting the possibility of slowing, halting and maybe reversing, neurodegeneration in Parkinson's or Alzheimer's diseases. Increased levels of oxidative stress in the brain may be critical for the initiation and progress of neurodegeneration and selective inhibition of brain MAO could contribute importantly to lowering such stress. There are complex interactions between free iron levels in brain and MAO, which may have practical outcomes for depressive disorders. These aspects of MAO and its inhibition and some indication of how this important area of pharmacology and therapeutics might develop in the future are summarized in this review.
567 citations
TL;DR: Two peptide-based inhibitor analogues that block LSD1 are designed and synthesized and one contains a propargylamine functionality and shows time-dependent inactivation of LSD1, likely to serve as a useful tool in the study of histone modifications and chromatin remodeling.
Abstract: Histone demethylase LSD1 is a flavin-dependent amine oxidase that catalyzes the oxidative removal of one or two methyl groups from the methyl-lysine-4 side chain of histone H3. We have designed and synthesized two peptide-based inhibitor analogues that block LSD1. One of these inhibitors, compound 1, contains a propargylamine functionality and shows time-dependent inactivation of LSD1. Peptide substrate, diMeK4H3-21, protected LSD1 against inactivation by 1 in a concentration-dependent fashion. Mass spectrometric analysis showed that 1 forms a covalent interaction with FAD. Compound 1 did not detectably inhibit monoamine oxidase B in the concentration range studied. Compound 1 is thus a selective, mechanism-based inactivator of LSD1 and is likely to serve as a useful tool in the study of histone modifications and chromatin remodeling.
158 citations
TL;DR: Analysis of kinetic and structural data suggests the function of the "aromatic cage" in MAO to include a steric role in substrate binding and access to the flavin coenzyme and to increase the nucleophilicity of the substrate amine moiety is suggested.
Abstract: Current structural results of several flavin-dependent amine oxidizing enzymes including human monoamine oxidases A and B (MAO A and MAO B) show aromatic amino acid residues oriented approximately perpendicular to the flavin ring, suggesting a functional role in catalysis. In the case of human MAO B, two tyrosyl residues (Y398 and Y435) are found in the substrate binding site on the re face of the covalent flavin ring [Binda et al. (2002) J. Biol. Chem. 277, 23973−23976]. To probe the functional significance of this structure, Tyr435 in MAO B was mutated with the amino acids Phe, His, Leu, or Trp, the mutant proteins expressed in Pichia pastoris, and purified to homogeneity. Each mutant protein contains covalent FAD and exhibits a high level of catalytic functionality. No major alterations in active site structures are detected on comparison of their respective crystal structures with that of WT enzyme. The relative kcat/Km values for each mutant enzyme show Y435 > Y435F = Y435L = Y435H > Y435W. A similar...
139 citations
TL;DR: In this paper, "ready to drink" coffee brews exhibited inhibitory properties on recombinant human MAO A and B isozymes catalyzing the oxidative deamination of kynuramine, suggesting that coffee contains compounds acting as MAO inhibitors.
132 citations
TL;DR: In this article, the major enzymes that catalyze the oxidative deamination of monoamine neurotaransmitters such as dopamine (DA), noradrenaline, and serotonin in the central and peripheral nervous systems are mainly localized in glial cells.
Abstract: Monoamine oxidases A and B (MAO A and MAO B) are the major enzymes that catalyze the oxidative deamination of monoamine neurotaransmitters such as dopamine (DA), noradrenaline, and serotonin in the central and peripheral nervous systems. MAO B is mainly localized in glial cells. MAO B also oxidizes the xenobiotic 1-methyl-4-phenyl- 1,2,3,6-tetrahydropyridine (MPTP) to a parkinsonism-producing neurotoxin, 1-methyl-4-phenyl-pyridinium (MPP+). MAO B may be closely related to the pathogenesis of Parkinson’s disease (PD), in which neuromelanincontaining DA neurons in the substantia nigra projecting to the striatum in the brain selectively degenerate. MAO B degrades the neurotransmitter DA that is deficient in the nigro-striatal region in PD, and forms H2O2 and toxic aldehyde metabolites of DA. H2O2 produces highly toxic reactive oxygen species (ROS) by Fenton reaction that is catalyzed by iron and neuromelanin. MAO B inhibitors such as L-(−)-deprenyl (selegiline) and rasagiline are effective for the treatment of PD. Concerning the mechanism of the clinical efficacy of MAO B inhibitors in PD, the inhibition of DA degradation (a symptomatic effect) and also the prevention of the formation of neurotoxic DA metabolites, i.e., ROS and dopamine derived aldehydes have been speculated. As another mechanism of clinical efficacy, MAO B inhibitors such as selegiline are speculated to have neuroprotective effects to prevent progress of PD. The possible mechanism of neuroprotection of MAO B inhibitors may be related not only to MAO B inhibition but also to induction and activation of multiple factors for anti-oxidative stress and anti-apoptosis: i.e., catalase, superoxide dismutase 1 and 2, thioredoxin, Bcl-2, the cellular poly(ADP-ribosyl)ation, and binding to glyceraldehydes-3-phosphate dehydrogenase (GAPDH). Furthermore, it should be noted that selegiline increases production of neurotrophins such as nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), and glial cell line-derived neurotrphic factor (GDNF), possibly from glial cells, to protect neurons from inflammatory process.
123 citations
TL;DR: "Several M A 0 inhibitors were tested for their influence on convulsions produced in rats by supramaximal elec t ro~hock", and three irreversibly acting inhibitors were studied.
Abstract: In contrast to most sedative drugs, reserpine lowers the threshold for electroshockor pentylenetetrazol-induced convulsions in mice." Since monoamine oxidase (MAO) inhibitors elevate the levels of brain serotonin (5-HT) and norepinephrine (NE), whereas reserpine lowers the levels, it occurred to us that M A 0 inhibitors might act as anticonvulsants. To explore this possibility, several M A 0 inhibitors were tested for their influence on convulsions produced in rats by supramaximal elec t ro~hock.~ Three irreversibly acting inhibitors were studied : iproniazid, JB-516, and JB-807.
113 citations
TL;DR: Structural-affinity and structure-selectivity relationships, derived through CoMFA-GOLPE and docking studies, revealed the key physicochemical interactions responsible for the observed MAO-B andMAO-A inhibitory potency and suggested the main structural determinants for high selectivity toward one of the two enzymatic isoforms.
Abstract: A new series of 3-, 4-, 7-polysubstituted coumarins have been designed and evaluated for their monoamine oxidase A and monoamine oxidase B (MAO-A and MAO-B) inhibitory potency. Substituents at position 7 consisted of a bridge of different physicochemical nature linking a phenyl ring to the coumarin scaffold. Structure−affinity and structure−selectivity relationships, derived through CoMFA-GOLPE and docking studies, revealed the key physicochemical interactions responsible for the observed MAO-B and MAO-A inhibitory potency and suggested the main structural determinants for high selectivity toward one of the two enzymatic isoforms. The predictive power of our models was proved with the design of a new inhibitor demonstrating an outstanding MAO-B affinity (pIC50 = 8.29) and the highest MAO-B selectivity (ΔpIC50 = 3.39) within the entire series of ligands examined herein.
99 citations
TL;DR: The results of a SAR study established that the potency of MAO-B inhibition by (E)-8-styrylcaffeinyl analogues depends upon the van der Waals volume, lipophilicity, and the Hammett constant.
76 citations
TL;DR: The results suggest that the rise in 5-HT is not the important factor in the excitation caused by MA0 inhibitors, but that N E might be.
Abstract: Accumulating evidence indicates that monoamine oxidase (MAO) is important in the metabolism of serotonin (5-HT) and norepinephrine (NE). Since these amines are substances of high biological activity and have been implicated in brain function, it becomes of great interest to see whether the antidepressant effects elicited by MA0 inhibitors are related to changes in the brain levels of these amine~.’-~ The effect of a single dose of iproniazid (Mardid)* (100 mg./kg.) on the brain amines is shown in FIGURE l:, The level of 5-HT rises over a period of 6 hours until it reaches a plateau about twice normal. The level of N E rises more slowly and to a somewhat lesser degree. No obvious pharmacological signs result from a single dose of the drug. Daily doses of 25 mg. of iproniazid/kg. also elevate 5-HT levels, which reach a plateau 2 to 3 times normal in 2 days, while N E again rises more slowly but finally, by the fourth day reaches a maximum level (TABLE l), which is somewhat higher than that obtained from the single large dose. At this time, the rabbits show definite sympathomimetic signs, including mydriasis, constriction of the blood vessels in the ear, and an increased motor activity. These effects disappear when the N E levels decline on cessation of drug administration, even though the 5-HT levels are still elevated. FIGURE 2 shows the effect of a single dose (2 mg./kg.) of the potent MA0 inhibitor JB-516 (phenylisopropylhydrazine).6* The 5-HT rises more rapidly than after iproniazid, reaching its maximum level in about 1 hour; the N E levels again rise more slowly and to a lesser degree. Here, too, no pharmacological effects are evident. The administration of JB-516 in daily doses of 2 mg./kg. elevates the 5-HT levels no higher than does the single dose but, by the fourth day, it elicits appreciably higher NE levels (TABLE 2). The animals now exhibit the same sympathomimetic signs as seen after repeated doses of iproniazid. When the drug administration is terminated the excitation again disappears when the N E levels decline, although the 5-HT levels are still elevated. The same pattern of response is seen with JB-835 (phenylisobutylhydrazine), another potent MA0 inhibitor that has activity comparable to that of JB-516 (FIGURE 3, TABLE 3). These results suggest that the rise in 5-HT is not the important factor in the excitation caused by MA0 inhibitors, but that N E might be. Further evidence of this is found in the failure of MA0 inhibitors to produce psychomotor activity in cats even after daily administration of the drugs for a period of 7 days. In this species the inhibitors induce a pronounced increase in brain
75 citations
Patent•
30 Jun 2006
TL;DR: In this article, the authors proposed novel compounds of formulae I and II: Formulae (I and II) that are monoamine oxidase-B inhibitors, which can be useful in treating obesity, diabetes, and/or cardiometabolic disorders.
Abstract: The invention provides novel compounds of formulae I and II: Formulae (I) and (II) that are monoamine oxidase-B inhibitors, which can be useful in treating obesity, diabetes, and/or cardiometabolic disorders (e.g., hypertension, dyslipidemias, high blood pressure, and insulin resistance).
70 citations
TL;DR: Results indicate that MAO‐A inhibition interacts with nicotine to enhance its rewarding effects in rats and suggest that other compounds present in tobacco, such as beta‐carboline, may also play an important role in sustaining smoking behavior in humans.
Abstract: Although nicotine is considered to be responsible for the addictive properties of tobacco, growing evidence underlines the importance of non-nicotine components in smoking reinforcement. It has been shown that tobacco smoke contains monoamine oxidase (MAO) A and B inhibitors and decreases MAO-A and MAO-B activity in smokers. Here, we investigated the effects of clorgyline hydrochloride (irreversible MAO-A inhibitor; 2 mg/kg/day), selegiline (irreversible MAO-B inhibitor; 4 mg/kg) and the beta-carboline norharmane hydrochloride (reversible MAO-B inhibitor; 5 mg/kg/day) treatments on nicotine self-administration (30 microg/kg/infusion, free base) in rats. Independent of the responsiveness to novelty and locomotor activity stimulation, only clorgyline hydrochloride treatment increased the intake of nicotine in a fixed-ratio schedule (FR5) of reinforcement. When a progressive-ratio schedule was implemented, both clorgyline hydrochloride and norharmane hydrochloride treatments potentiated the reinforcing effects of nicotine, whereas selegiline had no effect. Taken together, these results indicate that MAO-A inhibition interacts with nicotine to enhance its rewarding effects in rats and suggest that other compounds present in tobacco, such as beta-carboline, may also play an important role in sustaining smoking behavior in humans.
TL;DR: It is suggested that the stimulation of AADC gene expression may be relevant to the antiparkinsonian effects of MAO B inhibitors.
Abstract: The effect of some selective monoamine oxidase (MAO) inhibitors on aromatic L-amino acid decarboxylase (AADC) gene expression in PC12 cells has been examined. Irreversible MAO B inhibitors [(-)-deprenyl, pargyline, and MDL 72,974A] stimulated AADC gene expression, whereas a selective irreversible MAO A inhibitor (clorgyline) and a reversible MAO B inhibitor (Ro 19-6327) had no effect. Because there is no apparent MAO B activity in PC12 cells, it is postulated that there is a novel site of action for these MAO B inhibitors and that the pharmacological profile of this site matches that of neuroprotective MAO B inhibitors. Finally, it is suggested that the stimulation of AADC gene expression may be relevant to the antiparkinsonian effects of MAO B inhibitors.
TL;DR: A series of coumarin derivatives, bearing at the 7‐position ether, ketone, ester, carbamate, or amide functions of varying size and lipophilicity, were synthesized and investigated for their in vitro monoamine oxidase‐A and ‐B inhibitory activities.
Abstract: A series of coumarin derivatives (1-22), bearing at the 7-position ether, ketone, ester, carbamate, or amide functions of varying size and lipophilicity, were synthesized and investigated for their in vitro monoamine oxidase-A and -B (MAO-A and -B) inhibitory activities. Most of the compounds acted preferentially as MAO-B inhibitors, with IC(50) values in the micromolar to low-nanomolar range. A structure-activity-relationship (SAR) study highlighted lipophilicity as an important property modulating the MAO-B inhibition potency of 7-substituted coumarins, as shown by a linear correlation (n=20, r(2)=0.72) between pIC(50) and calculated log P values. The stability of ester-containing coumarin derivatives in rat plasma provided information on factors that either favor (lipophilicity) or decrease (steric hindrance) esterase-catalyzed hydrolysis. Two compounds (14 and 22) were selected to investigate how lipophilicity and enzymatic stability may affect in vivo MAO activities, as assayed ex vivo in rat. The most-potent and -selective MAO-B inhibitor 22 (=7-[(3,4-difluorobenzyl)oxy]-3,4-dimethyl-1-benzopyran-2(2H)-one) within the examined series significantly inhibited (>60%) ex vivo rat-liver and striatal MAO-B activities 1 h after intraperitoneal administration of high doses (100 and 300 mumol kg(-1)), revealing its ability to cross the blood-brain barrier. At the same doses, liver and striatum MAO-A was less inhibited in vivo, somehow reflecting MAO-B selectivity, as assessed in vitro. In contrast, the metabolically less stable derivative 14, bearing an isopropyl ester in the lateral chain, had a weak effect on hepatic MAO-B activity in vivo, and none on striatal MAO-B, but, surprisingly, displayed inhibitory effects on MAO-A in both peripheral and brain tissues.
TL;DR: Perinatal exposure to methylmercury and PCB153 results in regionally and/or gender-specific alterations in the central dopaminergic and serotonergic systems at weaning, which does not exacerbate the neurochemical effects of the individual compounds.
TL;DR: Although the exact mechanism of the anti-amyloidogenic activity of these agents is unclear, these and other structurally related compounds could be key molecules for the development of therapeutics for AD and other conformational diseases.
TL;DR: Selegiline increases the striatal superoxide dismutase, protects against peroxynitrite- and nitric oxide-induced apoptosis, and guards dopaminergic neurons from toxicity induced by glutathione depletion, and is neuroprotection in nature.
Abstract: Selegiline inhibits the activity of monoamine oxidase B, enhances the release of dopamine, blocks the uptake of dopamine, acts as a calmodulin antagonist, and enhances the level of cyclic AMP, which in turn protects dopaminergic neurons. It possesses cognition-enhancing functions, rejuvenates serum insulin-like growth factor I in aged rats, and enhances life expectancy in rodents. Selegiline possesses neurotrophic-like actions, and rescues axotomized motorneurons independent of monoamine oxidase B inhibition. It enhances the synthesis of nerve growth factor, protects dopaminergic neurons from glutamate-mediated neurotoxicity, and protects dopaminergic neurons from toxic factors present in the spinal fluid of parkinsonian patients, and the said effect may be mediated via elaborating brain derived neurotrophic factor. Selegiline increases the striatal superoxide dismutase, protects against peroxynitrite- and nitric oxide-induced apoptosis, and guards dopaminergic neurons from toxicity induced by glutathione depletion. It stimulates the biosynthesis of interleukin 1-beta and interleukin-6, is an immunoenhancing substance, possesses antiapoptotic actions, and is neuroprotectant in nature. Selegiline has been shown to be efficacious in Parkinson's disease, global ischemia, Gille de la Tourette syndrome, and narcolepsy. Its therapeutic efficacy in Alzheimer's disease remains uncertain. In Alzheimer's disease, short term studies of selegiline suggest a beneficial effect; whereas long term studies are less convincing.
TL;DR: K(i) values for the inhibition of human, baboon, monkey, dog, rat, and mouse liver MAO-B have been determined and the possibility of identifying novel structures of compounds that could lead to the development of neuroprotective agents is suggested.
TL;DR: Pargyline (M0911),* a non-hydrazide and potent M A 0 inhibitor which also has the advantage of being devoid of amphetamine-like properties was used to show the relationship between the central excitatory effect of MO 911 and the increase in brain NE.
Abstract: Interest in the role of monoamine oxidase (MAO) in the metabolism of brain norepinephrine (NE) and serotonin (5HT) has been stimulated by the findings that inhibitors of this enzyme can elevate the brain levels of both amines.l.2 The problem arises whether the behavioral effects produced after blockade of MA0 are limited to an increase in brain amines and whether they can be related to a particular amine. Our previous studies with hydrazides have indicated that the stimulation produced by M A 0 inhibitors is associated with the rise in brain NE and the consequent overspill of the amine onto receptor sites? It might well be argued that since hydrazides have a high chemical reactivity, the association is fortuitous and unrelated to blockade of MAO. Pargyline ( M0911),* a non-hydrazide and potent M A 0 inhibitor which also has the advantage of being devoid of amphetamine-like properties was used to show the relationship between the central excitatory effect of MO 911 and the increase in brain NE.
TL;DR: Clinicians should familiarize themselves with the properties and indications for the new generation of MAOIs and it is possible that STS may demonstrate benefit in MDD with atypical features or MDD resistant to other antidepressants.
Abstract: The clinical use of monoamine oxidase inhibitors (MAOIs) has declined due to concerns about food and drug interactions and waning physician experience. Evidence indicates that MAOIs are effective in depressive disorders, in particular depression with atypical features. Efforts to address safety issues have led to the development of more selective and reversible MAOIs, such as moclobemide. Selegiline, a selective monoamine oxidase B inhibitor, has been approved for the adjunctive treatment of Parkinson's disease at low doses. At higher doses, oral selegiline is also effective in major depressive disorder (MDD) but loses its selectivity and has the potential for tyramine interactions. To overcome these problems, a transdermal formulation of selegiline, the selegiline transdermal system (STS), was developed with novel pharmacokinetic and pharmacodynamic properties. Compared with oral administration, transdermal selegiline leads to sustained plasma concentrations of the parent compound, increasing the amount of drug delivered to the brain and decreasing metabolite production. In addition, STS allows targeted inhibition of central nervous system monoamine A (MAO-A) and monoamine B isoenzymes with minimal effects on MAO-A in the gastrointestinal and hepatic systems, thereby reducing the risk of interactions with tyramine-rich foods (the "cheese-reaction"). Clinical trials have found 6 mg/24 hours of STS to be effective in MDD without the need for dietary restrictions. The efficacy and safety profile of STS supports its use in MDD. It is possible that STS may demonstrate benefit in MDD with atypical features or MDD resistant to other antidepressants. However, more research is needed. Clinicians should familiarize themselves with the properties and indications for the new generation of MAOIs.
TL;DR: A test was devised whereby this enzymatic effect of a drug can be measured in the human and the relationship of MA0 inhibition to alterations in the blood pressure of patients with hypertension is investigated.
Abstract: I t is important to ascertain whether drugs which, on the basis of studies on animals, are called monoamine oxidase (MAO) inhibitors, do indeed inhibit this enzyme(s) in man in ordinary clinical dosage. To help solve this problem, a test was devised whereby this enzymatic effect of a drug can be measured in the human.l The test is based on the conversion of orally administered serotonin to 5-hydroxyindoleacetic acid (5-HIAA), which is the end product of MA0 activity on this amine. From a clinical standpoint, the effects of MA0 inhibitors on the cardiovascular system have been of particular interest to us. Since M A 0 is involved in the metabolism of several vasoactive monoamines, alterations in cardiovascular functions might be anticipated. It is noteworthy that iproniazid (Marsilid*) has been found to be useful in the treatment of angina pectoris2 and also hypertension3, in some patients. Certain other MA0 inhibitors also appear to have the property of lowering blood pressure in man. This presentation is concerned chiefly with the problem of measuring MA0 inhibition in man and the relationship of MA0 inhibition to alterations in the blood pressure of patients with hypertension.
TL;DR: The result suggests that l‐deprenyl may possess a unique neuroprotective action on nigral neuron against MPP+ toxicity independent of the MAO‐B inhibition.
Abstract: l-Deprenyl (Selegiline), a selective and irreversible type B monoamine oxidase inhibitor, has been used as an adjunct to levodopa therapy in Parkinson's disease. Recently, it is proposed as a putative neuroprotective agent in delaying the progression of cell death based on its capability of reducing the oxidative stress derived from the MAO-B dependent metabolism of dopamine, and blocking the development of MPTP-parkinsonism. However, a variety of experimental models suggest that l-deprenyl provides neuroprotection through multiple modes of mechanism other than the inhibition of MAO-B. We have previously shown that l-deprenyl protects midbrain dopamine neurons from MPP+ toxicity by a novel antioxidant effect. In the present study we examined whether the protection against MPP+ toxicity is also shared by other reversible or irreversible MAO-B inhibitors including (+)-deprenyl, Ro16-6491 and pargyline. Our data show that non of these MAO-B inhibitors changes the dopamine loss in the striatum induced by intranigral injection of MPP+. Our result suggests that l-deprenyl may possess a unique neuroprotective action on nigral neuron against MPP+ toxicity independent of the MAO-B inhibition.
TL;DR: 1H MRS is a sensitive measure of biochemical alterations of the brain in a mouse model of PD, and it is shown that the increases in striatal Lac/Cr ratio induced by MPTP may be associated with mitochondrial energy crisis, followed by dopaminergic neurotoxicity.
Abstract: Mitochondrial dysfunction has been implicated in the death of nigrostriatal dopaminergic neurons in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated experimental models of Parkinson's disease (PD). Here we utilized proton magnetic resonance spectroscopy ((1)H MRS) to identify changes in energy metabolism in the striatum of MPTP-treated C57BL/6 mice. Remarkable increases in lactate/creatine (Lac/Cr) ratio were observed at 2 h and then quickly returned to about the basal level by 7 h after injection of MPTP. Neurochemical and Western blot analyses revealed that dopamine contents and protein levels of tyrosine hydroxylase and dopamine transporter in the striatum were profoundly decreased at 3 days after MPTP treatment. Pretreatment with deprenyl, a monoamine oxidase B inhibitor, or GBR-12909, a dopamine uptake inhibitor, almost completely attenuated both the increases in striatal Lac/Cr ratio and the subsequent loss of dopaminergic nerve terminals in MPTP-treated mice. The present study indicates that (1)H MRS is a sensitive measure of biochemical alterations of the brain in a mouse model of PD, and further shows that the increases in striatal Lac/Cr ratio induced by MPTP may be associated with mitochondrial energy crisis, followed by dopaminergic neurotoxicity.
TL;DR: The results of some recent studies on the formation of the enzyme-substrate complex are reported to report the many gaps in the understanding of the basic enzymic event, the interaction between MA0 and its substrates, and to extend this line of investigation into the field of M A 0 inhibition.
Abstract: The first meeting dedicated exclusively to the discussion of monoamine oxidase inhibitors was held in November of 1957 in New York. One paper at this conference was introduced by a quotation about the stone which was rejected by the builders to become the cornerstone.' Doctor Kline was referring with this biblical verse2 to iproniazid (Marsilid) which was developed as an antituberculosis drug, but which later was dropped in favor of isoniazid and became all but forgotten until its use as an inhibitor of monoamine oxidase (MAO) spread into the fields of pharmacology, psychopharmacology, and therapy. Naturally, I am pleased that my laboratory had a chance to contribute to the rebirth of iproniazid by discovering, in 1952, its remarkable inhibitory power for MA0 in uitro and in u i ~ o . ~ In the following years we observed that iproniazid potentiated certain pharmacological effects of some sympathomimetic aminesaJ and that, when administered to schizophrenics, it induced simultaneous changes in the behavior and serotonin metabolism of the patients.8~~ The availability of M A 0 inhibitors apparently satisfied a great need and stimulated hundreds of investigations all over the world. The flood gates were opened by B. B. Brodie, A. Pletscher, and their coworkers and the stream of publications is still flowing rapidly (see references 10 and 11). The new tool helped to analyze the differences in the metabolic fates of endogenous us. exogenous amines. It was used in the discovery of new mammalian amines (e.g., octopamine) and it served in the elucidation of the mechanisms of reserpine and chlorpromazine and opened new fields in clinical research and therapy ( e.g., for Parkinson's disease). Among the thousands of compounds which were synthesized in order to obtain efficient blocking agents, several entirely new kinds of M A 0 inhibitors were discovered which proved to be of great help for in uitro and in uiuo studies and thus closed a cycle which began with and ended in enzymic analysis. At similar occasions12-16 various aspects of M A 0 [ Monoamine oxydoreductase ( deaminating ) , E.C. 1.4.3.41 were discussed: classification, distribution in nature, mode of action, parameters of in uitro and in uiuo inhibition, etc. In view of the many gaps in our understanding of the basic enzymic event, the interaction between MA0 and its substrates, it seem opportune to report the results of some recent studies on the formation of the enzyme-substrate complex and to extend this line of investigation into the field of M A 0 inhibition.
TL;DR: No correlation was noted between specific alleles and levels of MAO‐B activity in this sample set, suggesting that the structural gene for MAOB is not usually the primary determinant of activity levels in platelets.
Abstract: Genetic variations in monoamine oxidase (MAO)-B activity have been proposed to have a contributory role in several neurologic and psychiatric diseases. Variations in activity could affect rates of degradation of exogenous amines, including toxins, precursors of toxins (like 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine), or false transmitters, and of endogenous amines, such as neurotransmitters. In this study a highly polymorphic (GT)n repeat element was used to mark alleles at the MAOB locus. The MAOB allele status and levels of platelet MAO-B activity were determined for 41 control males. No correlation was noted between specific alleles and levels of MAO-B activity in this sample set. This suggests that the structural gene for MAOB is not usually the primary determinant of activity levels in platelets.
TL;DR: A number of investigators demonstrated that MA0 inhibition did not result in potentiation of epinephrine, norepinephrine, or nerve stimulation, and supported the view that M A 0 was not significantly involved in the inactivation of the catecholamines.
Abstract: In 1928, Hare-Bernheim demonstrated an enzyme that catalyzes the oxidative deamination of tyramine to p-hydroxybenzaldehyde, peroxide, and amm0nia.l I t was subsequently observed that t h i s enzyme, monoamine oxidase ( MAO) , deaminates many amines, including epinephrine and norepinephrine, to their corresponding aldehydes.2 The introduction by Zeller et aZ.3 of iproniazid, a potent MA0 inhibitor (MAOI), made possible examination of the role of t h i s enzyme in the metabolism and inactivation of the catecholamines. Using this drug, Griesemer et a2.4 found that inhibition of M A 0 in the intact animal prolonged the actions of tyramine and had no effect on the actions of administered epinephrine. Following this report a number of investigators demonstrated that MA0 inhibition did not result in potentiation of epinephrine, norepinephrine, or nerve stimulation.5~6J These reports supported the view that M A 0 was not significantly involved in the inactivation of the catecholamines. About the same time, however, another body of evidence was being accumulated which was interpreted as showing that MA0 did play an important role in the inactivation of the catecholamines. Schayer et aZ.* demonstrated that M A 0 was involved in some step in the metabolism of epinephrine. After the administration of (214-epinephrine labeled on the P-carbon, almost all of the administered radioactivity could be recovered from the urine. When N-methyl-C14-epinephririne was administered only 50 per cent of the radioactivity was found in the urine. However, rats pretreated with iproniazid excreted almost all of the radioactivity from Nmethy1-Cl4-epinephrine. It was concluded from t h i s data that MA0 played a major role in the metabolism of epinephrine. Whether deamination occurred on the epinephrine molecule itself or an amine-containing metabolite was not established at that time. Shore et a2.Q showed that inhibition of M A 0 resulted in increased tissue levels of endogenous norepinephrine and concluded that MA0 had a major role in the physiological inactivation of norepinephrine. At about this time, the metabolic fate of the catecholamines was being defined. Armstrong et aZ.10 identified 3-methoxy-4-hydroxymandelic acid (VMA) as a major excretion product of norepinephrine, and Axelrodll showed that 0-methylation of catecholamines could precede deamination and that this route of metabolism, rather than deamination, was the major means of metabolic inactivation of administered catecholamines. In mad2 and in rats13 only approximately one fourth of an administered dose of H3-
TL;DR: The results add to the evidence of involvement of MAOB in PD and suggest that the effect may be stronger in women, as a large family‐based data set was used to test associations between MAO genes and a risk of PD.
Abstract: Monoamine oxidase (MAO) is an enzyme regulating metabolism of neurotransmitters such as dopamine. Two distinct forms of enzyme, encoded by genes MAOA and MAOB located on the X chromosome, have been considered as possible factors in the pathogenesis of Parkinson disease (PD). Previous association studies of PD and MAO genes reported inconsistent results. In this study, we used a large family-based data set to test associations between MAO genes and a risk of PD. The data set includes 298 female discordant sibpairs and 348 male discordant sibpairs. For this study, all subjects analyzed were white and families with known parkin mutations were removed. We analyzed 15 single nucleotide polymorphisms (SNPs) and a dinucleotide repeat marker in the MAO genes. Association was found with the intron 13 SNP of MAOB in the female subset (P = 0.02). No significant association was found in the male subset. Our results add to the evidence of involvement of MAOB in PD and suggest that the effect may be stronger in women.
TL;DR: By chemically manipulating these endogenous substances the authors had been able to hand-control certain bodily processes that had begun to malfunction because of a breakdown in the once carefully balanced automatic control mechanism (homeostatic equilibrium) of the body.
Abstract: The advent of the tranquilizing drugs brought about a definite change in the philosophy of the treatment of mental disease. At least two benefits accrued from this change in our thinking: (1) it pointed a way toward the eventual physiological treatment of mental disease, and (2) it raised the possibility that certain therapeutic concepts and techniques that had dealt successfully with diseases other than mental could be extended and applied in the treatment of psychiatric disorders. The concepts to which I refer concern themselves primarily with the roles of such familiar chemical mediators of normal and abnormal physiological functions as acetylcholine, norepinephrine, epinephrine, histamine, and serotonin, as well as with the variety of approaches of potentiating and inhibiting their pharmacological effects. In other words, by chemically manipulating these endogenous substances we had been able to hand-control certain bodily processes that had begun to malfunction because of a breakdown in the once carefully balanced automatic control mechanism (homeostatic equilibrium) of the body. Diseases such as peptic ulcer, ulcerative colitis, biliary disorders, hypertension, allergic manifestations, and asthma could be treated in this fashion, a t least symptomatically. The work of Brodie,l Woolley,2 G a d d ~ m , ~ and Mills and Slater4 indicated that similar physiological mechanisms might be operating in the brain, and that their potentiation or inhibition might result in a practical approach to the treatment of mental disease. In the light of these concepts I shall review briefly the subject of central stimulants and then present in greater detail some of the newer approaches to the chemotherapy of the depressive state that are being attempted in our laboratories. The status of the central stimulants up to 1955 was perhaps adequately summed up by Goodman and Gilman5 in the second edition of The PharmacoZogical Basis o j Therapeufics : “Although central nervous system stimulants are sometimes dramatic in their pharmacological effects, they are relatively unimportant from a therapeutic point of view. It is not possible to stimulate the central nervous system for a long period of time, for heightened nervous activity is followed by depression, proportional in degree to the intensity and duration of the stimulation. Consequently, therapeutic excitation of the central nervous system is usually of brief duration and is reserved for emergencies characterized by severe central depres~ion.”~ This statement was based, of course, on the action of those drugs available a t the time for stimulation of the central nervous system (CNS). Such agents are picrotoxin, metrazol, strychnine, camphor, nikethamide, and caffeine. Picrotoxin and metrazol were used most often in respiratory depression resulting from barbiturate poisoning. Metrazol and camphor were, of course,
TL;DR: Novel effects of BU 224 and 2-BFI different from their already reported actions on brain or endocrine pancreas are demonstrated on WAT.
TL;DR: The findings suggest that the electrophilic nomifensine dihydroisoquinolinium metabolite, which can be generated by several enzymes, could be behind toxic responses to nomifenine such as hemolytic anemia and hepatotoxicity.
Abstract: Nomifensine is an antidepressant agent that was removed from use because of a high incidence of hemolytic anemia. It contains an N-methyl-8-aminotetrahydroisoquinoline ring which has the potential to be oxidized to quaternary dihydroisoquinolinium and isoquinolinium ions, albeit such a transformation had not been previously observed. In this report, we demonstrate the conversion of nomifensine to a dihydroisoquinolinium ion metabolite by several human enzymes. Human liver microsomes supplemented with NADPH generated the dihydroisoquinolinium ion metabolite along with other hydroxylated metabolites, whereas when supplemented with t-butyl peroxide, only the dihydroisoquinolinium ion metabolite was observed. Monoamine oxidase A, but not monoamine oxidase B, catalyzed this reaction, as well as human hemoglobin supplemented with H2O2. Human myeloperoxidase catalyzed this reaction in the presence of H2O2, and activation of the reaction was observed when incubations were conducted in the presence of acetaminophen at concentrations relevant to those measured in humans. The reaction was also observed in human whole blood. The equilibrium between the dihydroisoquinolinium ion and carbinolamine was shown to have a pK of about 11.7. The dihydroisoquinolinium ion was shown to react with cyanide and borohydride, but not glutathione. These findings suggest that the electrophilic nomifensine dihydroisoquinolinium metabolite, which can be generated by several enzymes, could be behind toxic responses to nomifensine such as hemolytic anemia and hepatotoxicity.