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Organic Letters Jul 2021We report here a three-component, Cu(I)-catalyzed hexadehydro-Diels-Alder (HDDA) benzyne 1,2-difunctionalization reaction. This protocol allowed the introduction of two...
We report here a three-component, Cu(I)-catalyzed hexadehydro-Diels-Alder (HDDA) benzyne 1,2-difunctionalization reaction. This protocol allowed the introduction of two different carbon-based substituents onto the in situ-generated benzyne. These substituents were terminal monoynes or diynes partnered with propargylic, benzylic, or allylic chlorides. An example of a sequential HDDA reaction is demonstrated using the product of a 1,3-diyne and a propargylic halide, itself a newly created HDDA precursor.
Topics: Benzene Derivatives; Catalysis; Copper; Cycloaddition Reaction; Diynes; Molecular Structure; Pargyline
PubMed: 34180676
DOI: 10.1021/acs.orglett.1c01788 -
Japanese Journal of Pharmacology Sep 1996The effects of harmaline on tryptophan-induced 5-hydroxytryptamine (5HT) syndrome and body temperature changes in pargyline-pretreated rats were investigated. When...
The effects of harmaline on tryptophan-induced 5-hydroxytryptamine (5HT) syndrome and body temperature changes in pargyline-pretreated rats were investigated. When administered i.p. 60 min after pargyline treatment (50 mg/kg, i.p.), tryptophan, at 100 mg/kg but not 10 mg/kg, induced the 5-HT syndrome. Tryptophan at 100 mg/kg also produced hypothermia followed by hyperthermia in pargyline-pretreated rats. Administration of harmaline (10 mg/kg, i.p.) 30 min after pargyline not only potentiated the 100 mg/kg tryptophan-induced 5-HT syndrome and body temperature changes, but also produced the syndrome following administration of 10 mg/kg tryptophan in pargyline-pretreated rats. In contrast, when administered 30 min before parygline, 10 mg/kg harmaline completely suppressed the syndrome and body temperature changes caused by mg/kg tryptophan. Tryptophan (100 mg/kg, i.p.) administration significantly increased 5-HT levels and decreased 5-hydroxyindole acetic and levels and 5-HT turnover in the brain of pargyline-pretreated rats. Harmaline administration 30 min after pargyline did not significantly affect the tryptophan-induced changes in 5-HT levels and 5-HT turnover, whereas when administered 30 min before pargyline, harmaline significantly blocked the effect of tryptophan. These results suggest that mechanisms underlying the inhibitory action of harmaline on the tryptophan-induced 5-HT syndrome and body temperature changes in pargyline-pretreated rats differ from those by which harmaline potentiates the effects of tryptophan.
Topics: Analysis of Variance; Animals; Behavior, Animal; Body Temperature Regulation; Harmaline; Male; Monoamine Oxidase Inhibitors; Pargyline; Rats; Rats, Wistar; Serotonin; Syndrome; Tryptophan
PubMed: 8902598
DOI: 10.1254/jjp.72.39 -
Physiological Research Dec 2019Increased activity of the sympathetic nervous system (SNS) has been proposed as a risk factor for increased cardiovascular mortality in patients with chronic kidney...
Increased activity of the sympathetic nervous system (SNS) has been proposed as a risk factor for increased cardiovascular mortality in patients with chronic kidney disease (CKD). Information on the activity of cardiac sympathetic innervation is non-homogeneous and incomplete. The aim of our study was to evaluate the tonic effect of SNS on heart rate, norepinephrine turnover and direct and indirect effects of norepinephrine in left ventricles of subtotally nephrectomized rats (SNX) in comparison with sham-operated animals (SHAM). Renal failure was verified by measuring serum creatinine and urea levels. SNX rats developed increased heart rates and blood pressure (BP). The increase in heart rate was not caused by sympathetic overactivity as the negative chronotropic effect of metipranolol did not differ between the SNX and SHAM animals. The positive inotropic effects of norepinephrine and tyramine on papillary muscle were not significantly different. Norepinephrine turnover was measured after the administration of tyrosine hydroxylase inhibitor, pargyline, tyramine, desipramine, and KCl induced depolarization. The absolute amount of released norepinephrine was comparable in both groups despite a significantly decreased norepinephrine concentration in the cardiac tissue of the SNX rats. We conclude that CKD associated with renal denervation in rats led to adaptive changes characterized by an increased reuptake and intracellular norepinephrine turnover which maintained normal reactivity of the heart to sympathetic stimulation.
Topics: Animals; Calcitonin Gene-Related Peptide; Cardiovascular Diseases; Disease Models, Animal; Heart Rate; Heart Ventricles; Kidney; Male; Nephrectomy; Neuropeptide Y; Norepinephrine; Rats, Wistar; Renal Insufficiency, Chronic; Sympathetic Nervous System
PubMed: 31928041
DOI: 10.33549/physiolres.934354 -
Pharmacology, Biochemistry, and Behavior Apr 2016Monoamine oxidase inhibitors (MAOIs) are often ingested together with tryptamine hallucinogens, but relatively little is known about the consequences of their combined...
Monoamine oxidase inhibitors (MAOIs) are often ingested together with tryptamine hallucinogens, but relatively little is known about the consequences of their combined use. We have shown previously that monoamine oxidase-A (MAO-A) inhibitors alter the locomotor profile of the hallucinogen 5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT) in rats, and enhance its interaction with 5-HT2A receptors. The goal of the present studies was to investigate the mechanism for the interaction between 5-MeO-DMT and MAOIs, and to determine whether other behavioral responses to 5-MeO-DMT are similarly affected. Hallucinogens disrupt prepulse inhibition (PPI) in rats, an effect typically mediated by 5-HT2A activation. 5-MeO-DMT also disrupts PPI but the effect is primarily attributable to 5-HT1A activation. The present studies examined whether an MAOI can alter the respective contributions of 5-HT1A and 5-HT2A receptors to the effects of 5-MeO-DMT on PPI. A series of interaction studies using the 5-HT1A antagonist WAY-100,635 and the 5-HT2A antagonist MDL 11,939 were performed to assess the respective contributions of these receptors to the behavioral effects of 5-MeO-DMT in rats pretreated with an MAOI. The effects of MAO-A inhibition on the pharmacokinetics of 5-MeO-DMT and its metabolism to bufotenine were assessed using liquid chromatography-electrospray ionization-selective reaction monitoring-tandem mass spectrometry (LC-ESI-SRM-MS/MS). 5-MeO-DMT (1mg/kg) had no effect on PPI when tested 45-min post-injection but disrupted PPI in animals pretreated with the MAO-A inhibitor clorgyline or the MAO-A/B inhibitor pargyline. The combined effect of 5-MeO-DMT and pargyline on PPI was antagonized by pretreatment with either WAY-100,635 or MDL 11,939. Inhibition of MAO-A increased the level of 5-MeO-DMT in plasma and whole brain, but had no effect on the conversion of 5-MeO-DMT to bufotenine, which was found to be negligible. The present results confirm that 5-MeO-DMT can disrupt PPI by activating 5-HT2A, and indicate that MAOIs alter 5-MeO-DMT pharmacodynamics by increasing its accumulation in the central nervous system.
Topics: Animals; Behavior, Animal; Drug Interactions; Hallucinogens; Male; Methoxydimethyltryptamines; Monoamine Oxidase Inhibitors; Rats; Rats, Sprague-Dawley; Receptor, Serotonin, 5-HT1A; Receptor, Serotonin, 5-HT2A; Reflex, Startle
PubMed: 26780349
DOI: 10.1016/j.pbb.2016.01.005 -
Oncology Reports Oct 2013Chemotherapy is one of the therapeutic strategies that has been used for the inhibition of cancer cell proliferation in several types of cancer, including prostate...
Chemotherapy is one of the therapeutic strategies that has been used for the inhibition of cancer cell proliferation in several types of cancer, including prostate cancer. Although monoamine oxidase (MAO) inhibitors, phytoestrogen and antioxidants used in chemotherapy have been systematically studied, their effects on cancer cell growth remain to be fully understood. The purpose of this study was to investigate the effects of the MAO inhibitors, pargyline and tranylcypromine on cell survival in human prostate carcinoma (LNCaP-LN3) cells. After treating LNCaP-LN3 cells with pargyline or tranylcypromine, we examined cell proliferation, cell cycle pattern, apoptosis and the expression levels of apoptosis-related genes. The proliferation of cells exposed to pargyline decreased in a dose- and time-dependent manner, while tranylcypromine-treated cells showed the opposite results. Treatment with pargyline significantly induced cell cycle arrest at the G1 phase compared to the control and tranylcypromine-treated cells. In addition, pargyline induced an increase in the cell death rate by promoting apoptosis; however, tranylcypromine had no effect on LNCaP-LN3 cells. Based on our results, we suggest that pargyline is more powerful than tranylcypromine for the treatment of human prostate cancer.
Topics: Apoptosis; Caspase 3; Cell Cycle; Cell Line, Tumor; Cell Proliferation; Cell Survival; Cytochromes c; G1 Phase Cell Cycle Checkpoints; Humans; Male; Monoamine Oxidase Inhibitors; Pargyline; Prostatic Neoplasms; Proto-Oncogene Proteins c-bcl-2; RNA, Messenger; Tranylcypromine
PubMed: 23900512
DOI: 10.3892/or.2013.2635 -
European Journal of Nuclear Medicine... Sep 2022[F]-labeled positron emission tomography (PET) radioligands permit in vivo assessment of Alzheimer's disease biomarkers, including aggregated neurofibrillary tau (NFT)...
PURPOSE
[F]-labeled positron emission tomography (PET) radioligands permit in vivo assessment of Alzheimer's disease biomarkers, including aggregated neurofibrillary tau (NFT) with [F]flortaucipir. Due to structural similarities of flortaucipir with some monoamine oxidase A (MAO-A) inhibitors, this study aimed to evaluate flortaucipir binding to MAO-A and MAO-B and any potential impact on PET interpretation.
METHODS
[F]Flortaucipir autoradiography was performed on frozen human brain tissue slices, and PET imaging was conducted in rats. Dissociation constants were determined by saturation binding, association and dissociation rates were measured by kinetic binding experiments, and IC values were determined by competition binding.
RESULTS
Under stringent wash conditions, specific [F]flortaucipir binding was observed on tau NFT-rich Alzheimer's disease tissue and not control tissue. In vivo PET experiments in rats revealed no evidence of [F]flortaucipir binding to MAO-A; pre-treatment with MAO inhibitor pargyline did not impact uptake or wash-out of [F]flortaucipir. [F]Flortaucipir bound with low nanomolar affinity to human MAO-A in a microsomal preparation in vitro but with a fast dissociation rate relative to MAO-A ligand fluoroethyl-harmol, consistent with no observed in vivo binding in rats of [F]flortaucipir to MAO-A. Direct binding of flortaucipir to human MAO-B was not detected in a microsomal preparation. A high concentration of flortaucipir (IC of 1.3 μM) was found to block binding of the MAO-B ligand safinamide to MAO-B on microsomes suggesting that, at micromolar concentrations, flortaucipir weakly binds to MAO-B in vitro.
CONCLUSION
These data suggest neither MAO-A nor MAO-B binding will contribute significantly to the PET signal in cortical target areas relevant to the interpretation of [F]flortaucipir.
Topics: Alzheimer Disease; Animals; Brain; Carbolines; Humans; Ligands; Monoamine Oxidase; Monoamine Oxidase Inhibitors; Positron-Emission Tomography; Rats; tau Proteins
PubMed: 35596745
DOI: 10.1007/s00259-022-05822-9 -
Molecular Neurodegeneration Jan 2016Mitochondrial dysfunction, oxidative stress and their interplay are core pathological features of Parkinson's disease. In dopaminergic neurons, monoamines and their...
BACKGROUND
Mitochondrial dysfunction, oxidative stress and their interplay are core pathological features of Parkinson's disease. In dopaminergic neurons, monoamines and their metabolites provide an additional source of reactive free radicals during their breakdown by monoamine oxidase or auto-oxidation. Moreover, mitochondrial dysfunction and oxidative stress have a supraadditive impact on the pathological, cytoplasmic accumulation of dopamine and its subsequent release. Here we report the effects of a novel series of potent and selective MAO-B inhibitory (hetero)arylalkenylpropargylamine compounds having protective properties against the supraadditive effect of mitochondrial dysfunction and oxidative stress.
RESULTS
The (hetero)arylalkenylpropargylamines were tested in vitro, on acute rat striatal slices, pretreated with the complex I inhibitor rotenone and in vivo, using the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) induced acute, subchronic, and chronic experimental models of Parkinson's disease in mice. The compounds exhibited consistent protective effects against i) in vitro oxidative stress induced pathological dopamine release and the formation of toxic dopamine quinone in the rat striatum and rescued tyrosine hydroxylase positive neurons in the substantia nigra after rotenone treatment; ii) in vivo MPTP-induced striatal dopamine depletion and motor dysfunction in mice using acute and subchronic, delayed application protocols. One compound (SZV558) was also examined and proved to be protective in a chronic mouse model of MPTP plus probenecid (MPTPp) administration, which induces a progressive loss of nigrostriatal dopaminergic neurons.
CONCLUSIONS
Simultaneous inhibition of MAO-B and oxidative stress induced pathological dopamine release by the novel propargylamines is protective in animal models and seems a plausible strategy to combat Parkinson's disease.
Topics: Animals; Corpus Striatum; Disease Models, Animal; Dopamine; Dopaminergic Neurons; Male; Oxidative Stress; Pargyline; Parkinson Disease; Propylamines; Rats, Wistar; Substantia Nigra
PubMed: 26758813
DOI: 10.1186/s13024-015-0067-y -
Journal of Neurochemistry Oct 1997This study was undertaken, using microdialysis, to compare the extracellular concentration of 3-methoxytyramine and dopamine in dialysate from the striatum and...
This study was undertaken, using microdialysis, to compare the extracellular concentration of 3-methoxytyramine and dopamine in dialysate from the striatum and substantia nigra, after pargyline (75 mg/kg), after pargyline plus amphetamine (3 mg/kg), and after pargyline plus reserpine (5 mg/kg) administration. Treatment with pargyline alone increased the extracellular dopamine concentration by 70% in the striatum and by 140% in the substantia nigra and induced in both regions a time-dependent accumulation of 3-methoxytyramine. The addition of d-amphetamine to pargyline increased the extracellular dopamine concentration, compared with pargyline-treated controls, to the same extent in both the substantia nigra (maximally by 360%) and the striatum (maximally by 400%), but the concomitant increase of 3-methoxytyramine accumulation in the dialysate was relatively smaller in the substantia nigra compared with the striatum. Reserpine treatment decreased the extracellular dopamine concentration in both regions below the detection level (<10% of basal value). When pargyline was added to reserpine, the striatal extracellular dopamine concentration increased to 50% of pargyline-treated controls and the striatal 3-methoxytyramine accumulation was less than in pargyline-treated controls. However, in the substantia nigra, the addition of pargyline to reserpine resulted in dopamine concentrations as high as after pargyline only and the 3-methoxytyramine accumulation was not changed compared with pargyline-treated controls. In summary, our results indicate that dopamine in the substantia nigra is released from reserpine-sensitive storage sites and that pargyline-induced 3-methoxytyramine accumulation is a poor indicator of the local dopamine release. The latter observation may be explained by the fact that the dopamine-metabolizing enzyme, catechol-O-methyltransferase, is located inter alia in the dopamine-containing cell bodies/dendrites in the substantia nigra, in contrast to the situation in the terminals in the striatum where catechol-O-methyltransferase is located only in nondopaminergic cells.
Topics: 3,4-Dihydroxyphenylacetic Acid; Animals; Dendrites; Dextroamphetamine; Dopamine; Dopamine Agents; Drug Combinations; Extracellular Space; Homovanillic Acid; Male; Monoamine Oxidase Inhibitors; Osmolar Concentration; Pargyline; Rats; Rats, Sprague-Dawley; Reserpine; Substantia Nigra
PubMed: 9326297
DOI: 10.1046/j.1471-4159.1997.69041684.x -
World Journal of Diabetes Jan 2022When combined with vanadium salts, catecholamines strongly activate glucose uptake in rat and mouse adipocytes.
BACKGROUND
When combined with vanadium salts, catecholamines strongly activate glucose uptake in rat and mouse adipocytes.
AIM
To test whether catecholamines activate glucose transport in human adipocytes.
METHODS
The uptake of 2-deoxyglucose (2-DG) was measured in adipocytes isolated from pieces of abdominal subcutaneous tissue removed from women undergoing reconstructive surgery. Pharmacological approaches with amine oxidase inhibitors, adrenoreceptor agonists and antioxidants were performed to unravel the mechanisms of action of noradrenaline or adrenaline (also named epinephrine).
RESULTS
In human adipocytes, 45-min incubation with 100 µmol/L adrenaline or noradrenaline activated 2-DG uptake up to more than one-third of the maximal response to insulin. This stimulation was not reproduced with millimolar doses of dopamine or serotonin and was not enhanced by addition of vanadate to the incubation medium. Among various natural amines and adrenergic agonists tested, no other molecule was more efficient than adrenaline and noradrenaline in stimulating 2-DG uptake. The effect of the catecholamines was not impaired by pargyline and semicarbazide, contrarily to that of benzylamine or methylamine, which are recognized substrates of semicarbazide-sensitive amine oxidase. Hydrogen peroxide at 1 mmol/L activated hexose uptake but not pyrocatechol or benzoquinone, and only the former was potentiated by vanadate. Catalase and the phosphoinositide 3-kinase inhibitor wortmannin inhibited adrenaline-induced activation of 2-DG uptake.
CONCLUSION
High doses of catecholamines exert insulin-like actions on glucose transport in human adipocytes. At submillimolar doses, vanadium did not enhance this catecholamine activation of glucose transport. Consequently, this dismantles our previous suggestion to combine the metal ion with catecholamines to improve the benefit/risk ratio of vanadium-based antidiabetic approaches.
PubMed: 35070058
DOI: 10.4239/wjd.v13.i1.37 -
Molekuliarnaia Biologiia 2021Fundamental neurophysiological processes are often studied using Danio rerio fish as a model. A selective inhibitor of striatal-enriched protein tyrosine phosphatase...
Fundamental neurophysiological processes are often studied using Danio rerio fish as a model. A selective inhibitor of striatal-enriched protein tyrosine phosphatase (STEP) reduces serotonin metabolism in the D. rerio brain. Both STEP and serotonin are involved in the development of neurodegenerative behavioral disorders. Reduction or elevation of the serotonin level in the brain of mice caused by the administration of p-chlorophenylalanine or pargyline, respectively, results in a decrease in the level of ptpn5 mRNA in the striatum, ptpn5 being the gene encoding STEP. However, it has not been established whether this occurs in other organisms. We studied the effect of inhibitors of synthesis (p-chlorophenylalanine) and degradation (pargyline) of serotonin on the expression of the ptpn5 gene and the activity of STEP in the brain of D. rerio. The fish were placed in water containing p-chlorophenylalanine (2 mg/L) or pargyline (0.5 mg/L) for 72 hours, and control subjects were kept in aquarium water. The p-chlorophenylalanine treatment decreased the serotonin level in the brain fourfold, whereas pargyline increased the level of this transmitter sixfold. Both p-chlorophenylalanine and pargyline decrease STEP activity in the D. rerio brain, without affecting the level of the ptpn5 mRNA gene. Thus, interaction between STEP and the serotonin system is observed in both mammals and fish, which indicates the similarity of the regulation processes in vertebrates.
Topics: Animals; Brain; Fenclonine; Mice; Pargyline; Protein Tyrosine Phosphatases; Zebrafish
PubMed: 34432783
DOI: 10.31857/S0026898421030113