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Molecules (Basel, Switzerland) May 2024A versatile family of quaternary propargylamines was synthesized employing the KA multicomponent reaction, through the single-step coupling of a number of amines,...
A versatile family of quaternary propargylamines was synthesized employing the KA multicomponent reaction, through the single-step coupling of a number of amines, ketones, and terminal alkynes. Sustainable synthetic procedures using transition metal catalysts were employed in all cases. The inhibitory activity of these molecules was evaluated against human monoaminoxidase (hMAO)-A and hMAO-B enzymes and was found to be significant. The IC values for hMAO-B range from 152.1 to 164.7 nM while the IC values for hMAO-A range from 765.6 to 861.6 nM. Furthermore, these compounds comply with Lipinski's rule of five and exhibit no predicted toxicity. To understand their binding properties with the two target enzymes, key interactions were studied using molecular docking, all-atom molecular dynamics (MD) simulations, and MM/GBSA binding free energy calculations. Overall, herein, the reported family of propargylamines exhibits promise as potential treatments for neurodegenerative disorders, such as Parkinson's disease. Interestingly, this is the first time a propargylamine scaffold bearing an internal alkyne has been reported to show activity against monoaminoxidases.
Topics: Alkynes; Monoamine Oxidase; Monoamine Oxidase Inhibitors; Humans; Molecular Docking Simulation; Molecular Dynamics Simulation; Pargyline; Propylamines; Structure-Activity Relationship; Molecular Structure
PubMed: 38893361
DOI: 10.3390/molecules29112486 -
Brain Communications 2024Dravet syndrome is a severe genetic epilepsy primarily caused by mutations in a voltage-activated sodium channel gene (). Patients face life-threatening seizures that...
Dravet syndrome is a severe genetic epilepsy primarily caused by mutations in a voltage-activated sodium channel gene (). Patients face life-threatening seizures that are largely resistant to available anti-seizure medications. Preclinical Dravet syndrome animal models are a valuable tool to identify candidate anti-seizure medications for these patients. Among these, mutant zebrafish, exhibiting spontaneous seizure-like activity, are particularly amenable to large-scale drug screening. Thus far, we have screened more than 3000 drug candidates in zebrafish mutants, identifying valproate, stiripentol, and fenfluramine e.g. Food and Drug Administration-approved drugs, with clinical application in the Dravet syndrome population. Successful phenotypic screening in mutant zebrafish is rigorous and consists of two stages: (i) a locomotion-based assay measuring high-velocity convulsive swim behaviour and (ii) an electrophysiology-based assay, using local field potential recordings, to quantify electrographic seizure-like events. Historically, nearly 90% of drug candidates fail during translation from preclinical models to the clinic. With such a high failure rate, it becomes necessary to address issues of replication and false positive identification. Leveraging our zebrafish assays is one approach to address these problems. Here, we curated a list of nine anti-seizure drug candidates recently identified by other groups using preclinical Dravet syndrome models: 1-Ethyl-2-benzimidazolinone, AA43279, chlorzoxazone, donepezil, lisuride, mifepristone, pargyline, soticlestat and vorinostat. First-stage locomotion-based assays in mutant zebrafish identified only 1-Ethyl-2-benzimidazolinone, chlorzoxazone and lisuride. However, second-stage local field potential recording assays did not show significant suppression of spontaneous electrographic seizure activity for any of the nine anti-seizure drug candidates. Surprisingly, soticlestat induced frank electrographic seizure-like discharges in wild-type control zebrafish. Taken together, our results failed to replicate clear anti-seizure efficacy for these drug candidates highlighting a necessity for strict scientific standards in preclinical identification of anti-seizure medications.
PubMed: 38707709
DOI: 10.1093/braincomms/fcae135 -
Molecular Neurodegeneration Apr 2024Hypometabolism tied to mitochondrial dysfunction occurs in the aging brain and in neurodegenerative disorders, including in Alzheimer's disease, in Down syndrome, and in...
BACKGROUND
Hypometabolism tied to mitochondrial dysfunction occurs in the aging brain and in neurodegenerative disorders, including in Alzheimer's disease, in Down syndrome, and in mouse models of these conditions. We have previously shown that mitovesicles, small extracellular vesicles (EVs) of mitochondrial origin, are altered in content and abundance in multiple brain conditions characterized by mitochondrial dysfunction. However, given their recent discovery, it is yet to be explored what mitovesicles regulate and modify, both under physiological conditions and in the diseased brain. In this study, we investigated the effects of mitovesicles on synaptic function, and the molecular players involved.
METHODS
Hippocampal slices from wild-type mice were perfused with the three known types of EVs, mitovesicles, microvesicles, or exosomes, isolated from the brain of a mouse model of Down syndrome or of a diploid control and long-term potentiation (LTP) recorded. The role of the monoamine oxidases type B (MAO-B) and type A (MAO-A) in mitovesicle-driven LTP impairments was addressed by treatment of mitovesicles with the irreversible MAO inhibitors pargyline and clorgiline prior to perfusion of the hippocampal slices.
RESULTS
Mitovesicles from the brain of the Down syndrome model reduced LTP within minutes of mitovesicle addition. Mitovesicles isolated from control brains did not trigger electrophysiological effects, nor did other types of brain EVs (microvesicles and exosomes) from any genotype tested. Depleting mitovesicles of their MAO-B, but not MAO-A, activity eliminated their ability to alter LTP.
CONCLUSIONS
Mitovesicle impairment of LTP is a previously undescribed paracrine-like mechanism by which EVs modulate synaptic activity, demonstrating that mitovesicles are active participants in the propagation of cellular and functional homeostatic changes in the context of neurodegenerative disorders.
Topics: Humans; Animals; Mice; Extracellular Space; Down Syndrome; Neuronal Plasticity; Brain; Alzheimer Disease; Disease Models, Animal; Monoamine Oxidase; Mitochondrial Diseases
PubMed: 38616258
DOI: 10.1186/s13024-024-00721-z -
Journal of Chromatography. B,... May 2024Trace amines are powerful neuromodulators influencing the release and reuptake of catecholamines. These low concentrated endogenous amines impact mood, cognition, and...
OBJECTIVES
Trace amines are powerful neuromodulators influencing the release and reuptake of catecholamines. These low concentrated endogenous amines impact mood, cognition, and hormone regulation. Dysregulation of trace amines have been associated with a variety of diseases, such as schizophrenia, Parkinson's disease, migraine, depression and more. Succesfull simultaneous quantification of trace amines, their precursors and metabolites would benefit both research and patient care. Since these compounds have various functional groups and are present in biological matrices with large concentration difference, their simultaneous quantification is an analytical challenge. Our goal was to develop a highly sensitive LC-MS/MS assay to simultaneously quantify trace amines, their precursors and metabolites in plasma.
METHODS
Our method is based on a simple two-step in-matrix derivatization protocol: propionic anhydride (PA) and 3-Ethyl-1-[3-(dimethylamino)propyl]carbodiimide (EDC) in combination with 2,2,2-trifluoroethylamine (TFEA) followed by online solid phase extraction combined with LC-MS/MS. Fifteen metabolites can be measured simultaneously, three precursors, eight trace amines and four metabolites. Validation of this method was performed according to international validation guidelines. The pre-analytical stability of trace amines was assessed.
RESULTS
This novel method was successful in quantifying trace amines, their precursors, and metabolites in plasma. Using just 50 µl human plasma, we were able to accomplish limit of quantification for 2-phenylethylamine and N-methyl-phenylethylamine of 0.2 nmol/L and 0.1 nmol/L for tyramine and n-methyltyramine. Inter-and intra-assay imprecision was < 15 % for all analytes. Stability assessment showed susceptibility of certain trace amines e.g. 2-phenylethylamine and N-methyl-phenylethylamine to enzymatic degradation in plasma. The addition of the monoamine oxidase inhibitor pargyline to plasma prevented this enzymatic degradation.
CONCLUSIONS
We developed a novel LC-MS/MS method that1) uses a new double derivatization technique, 2) is automated with online SPE, 3) uses far less sample volume then previous methods and 4) detects more components in the same sample (eight trace amines, three precursors, and four metabolites) with high specificity and selectivity. Furthermore, addition of MAO A/B inhibitor prevents degradation and guarantees more accurate quantification of trace amines.
Topics: Humans; Tandem Mass Spectrometry; Reproducibility of Results; Amines; Chromatography, Liquid; Limit of Detection; Linear Models; Solid Phase Extraction
PubMed: 38583227
DOI: 10.1016/j.jchromb.2024.124098 -
BioRxiv : the Preprint Server For... Nov 2023Dravet syndrome (DS) is a severe genetic epilepsy primarily caused by mutations in a voltage-activated sodium channel gene (SCN1A). Patients face life-threatening...
Dravet syndrome (DS) is a severe genetic epilepsy primarily caused by mutations in a voltage-activated sodium channel gene (SCN1A). Patients face life-threatening seizures that are largely resistant to available anti-seizure medications (ASM). Preclinical DS animal models are a valuable tool to identify candidate ASMs for these patients. Among these, mutant zebrafish exhibiting spontaneous seizure-like activity are particularly amenable to large-scale drug screening. Prior screening in a mutant zebrafish line generated using N-ethyl-Nnitrosourea (ENU) identified valproate, stiripentol, and fenfluramine e.g., Federal Drug Administration (FDA) approved drugs with clinical application in the DS population. Successful phenotypic screening in mutant zebrafish consists of two stages: (i) a locomotion-based assay measuring high-velocity convulsive swim behavior and (ii) an electrophysiology-based assay, using local field potential (LFP) recordings, to quantify electrographic seizure-like events. Using this strategy more than 3000 drug candidates have been screened in zebrafish mutants. Here, we curated a list of nine additional anti-seizure drug candidates recently identified in preclinical models: 1-EBIO, AA43279, chlorzoxazone, donepezil, lisuride, mifepristone, pargyline, soticlestat and vorinostat. First-stage locomotion-based assays in mutant zebrafish identified only 1-EBIO, chlorzoxazone and lisuride. However, second-stage LFP recording assays did not show significant suppression of spontaneous electrographic seizure activity for any of the nine anti-seizure drug candidates. Surprisingly, soticlestat induced frank electrographic seizure-like discharges in wild-type control zebrafish. Taken together, our results failed to replicate clear anti-seizure efficacy for these drug candidates highlighting a necessity for strict scientific standards in preclinical identification of ASMs.
PubMed: 38014342
DOI: 10.1101/2023.11.11.566723 -
Molecules (Basel, Switzerland) Aug 2023Monoamine oxidase (MAO, EC 1.4.3.4) is responsible for the oxidative breakdown of both endogenous and exogenous amines and exists in MAO-A and MAO-B isomers. Eighteen...
Assembling a Cinnamyl Pharmacophore in the C3-Position of Substituted Isatins via Microwave-Assisted Synthesis: Development of a New Class of Monoamine Oxidase-B Inhibitors for the Treatment of Parkinson's Disease.
Monoamine oxidase (MAO, EC 1.4.3.4) is responsible for the oxidative breakdown of both endogenous and exogenous amines and exists in MAO-A and MAO-B isomers. Eighteen indole-based phenylallylidene derivatives were synthesized via nucleophilic addition reactions comprising three sub-series, , , and , and were developed and examined for their ability to inhibit MAO. Among them, compound showed a strong MAO-B inhibitory effect with an IC () value of 1.672 μM, followed by (IC = 16.934 μM). Additionally, showed the highest selectivity index (SI) value of >23.92. The effectiveness of was lower than the reference pargyline (0.14 μM); however, the SI value was higher than pargyline (17.16). Structurally, the (-H in the B-ring) sub-series exhibited relatively stronger MAO-B inhibition than the others. In the series, (-F in the A-ring) exhibited stronger MAO-B suppression than the other substituted derivatives in the order -F > -Br > -Cl > -OCH, -CH, and -H at the 2-position in the A-ring. In the reversibility and enzyme kinetics experiments, was a reversible inhibitor with a K value of 0.51 ± 0.15 μM for MAO-B. Further, it was observed that greatly decreased the cell death caused by rotenone in SH-SY5Y neuroblastoma cells. A molecular docking study of the lead molecule was also performed to determine hypothetical interactions in the enzyme-binding cavity. These findings suggest that is a strong, specific, and reversible MAO-B inhibitor that can be used to treat neurological diseases.
Topics: Humans; Parkinson Disease; Isatin; Microwaves; Molecular Docking Simulation; Pargyline; Pharmacophore; Neuroblastoma; Dopamine Agents; Monoamine Oxidase; Antipsychotic Agents
PubMed: 37630420
DOI: 10.3390/molecules28166167 -
Organic Letters Jun 2023Base-mediated rearrangement of 1,3-dithianyl-substituted propargylamines in DMF via expansion of the dithiane ring has been reported. The rearrangement provided...
Base-mediated rearrangement of 1,3-dithianyl-substituted propargylamines in DMF via expansion of the dithiane ring has been reported. The rearrangement provided 9-membered amino-functionalized sulfur-containing heterocycles (dithionine derivatives) in good yields under mild conditions. Propargylamines bearing 5-membered 1,3-dithiolane and 7-membered 1,3-dithiepane rings rearranged in a similar manner yielding 8- and 10-membered -heterocycles, respectively.
Topics: Sulfur; Propylamines; Pargyline; Culture Media
PubMed: 37232086
DOI: 10.1021/acs.orglett.3c01118 -
Molecules (Basel, Switzerland) Feb 2023In this work, 2-alkyl-10-chloro-1,2,3,4-tetrahydrobenzo[][1,6]naphthyridines were obtained and their reactivity was studied. Novel derivatives of the tricyclic scaffold,...
In this work, 2-alkyl-10-chloro-1,2,3,4-tetrahydrobenzo[][1,6]naphthyridines were obtained and their reactivity was studied. Novel derivatives of the tricyclic scaffold, including 1-phenylethynyl (), 1-indol-3-yl (), and azocino[4,5-]quinoline () derivatives, were synthesized and characterized herein for the first time. Among the newly synthesized derivatives, - proved to be MAO B inhibitors with potency in the low micromolar range. In particular, the 1-(2-(4-fluorophenyl)ethynyl) analog achieved an IC of 1.35 μM, a value close to that of the well-known MAO B inhibitor pargyline.
Topics: Monoamine Oxidase Inhibitors; Pargyline; Monoamine Oxidase; Naphthyridines; Structure-Activity Relationship
PubMed: 36838649
DOI: 10.3390/molecules28041662 -
Naunyn-Schmiedeberg's Archives of... Jul 2023It is unclear whether bufotenin (= N,N-dimethyl-serotonin = 5-hydroxy-N,N-dimethyl-tryptamine), a hallucinogenic drug, can act on human cardiac serotonin 5-HT...
It is unclear whether bufotenin (= N,N-dimethyl-serotonin = 5-hydroxy-N,N-dimethyl-tryptamine), a hallucinogenic drug, can act on human cardiac serotonin 5-HT receptors. Therefore, the aim of the study was to examine the cardiac effects of bufotenin and for comparison tryptamine in transgenic mice that only express the human 5-HT receptor in cardiomyocytes (5-HT-TG), in their wild-type littermates (WT) and in isolated electrically driven (1 Hz) human atrial preparations. In 5-HT-TG, we found that both bufotenin and tryptamine enhanced the force of contraction in left atrial preparations (pD2 = 6.77 or 5.5, respectively) and the beating rate in spontaneously beating right atrial preparations (pD2 = 7.04 or 5.86, respectively). Bufotenin (1 µM) increased left ventricular force of contraction and beating rate in Langendorff perfused hearts from 5-HT-TG, whereas it was inactive in hearts from WT animals, as was tryptamine. The positive inotropic and chronotropic effects of bufotenin and tryptamine were potentiated by an inhibitor of monoamine oxidases (50 µM pargyline). Furthermore, bufotenin concentration- (0.1-10 µM) and time-dependently elevated force of contraction in isolated electrically stimulated musculi pectinati from the human atrium and these effects were likewise reversed by tropisetron (10 µM). We found that bufotenin (10 µM) increased the phosphorylation state of phospholamban in the isolated perfused hearts, left and right atrial muscle strips of 5-HT-TG but not from WT and in isolated human right atrial preparations. In summary, we showed that bufotenin can increase the force of contraction via stimulation of human 5-HT receptors transgenic mouse cardiac preparations but notably also in human atrial preparations.
Topics: Mice; Animals; Humans; Serotonin; Mice, Transgenic; Bufotenin; Atrial Fibrillation; Myocardial Contraction; Receptors, Serotonin, 5-HT4; Heart Atria; Receptors, Serotonin
PubMed: 36754881
DOI: 10.1007/s00210-023-02414-8 -
International Journal of Molecular... Nov 2022Serotonin (5-HT) plays an essential role in regulating female reproductive function in many animals. 5-HT accumulates in the mammalian ovary with the involvement of...
Serotonin (5-HT) plays an essential role in regulating female reproductive function in many animals. 5-HT accumulates in the mammalian ovary with the involvement of membrane serotonin transporter SERT and is functionally active in the oocytes of growing follicles, but shows almost no activity in follicular cells. In this study, we clarified the interplay between 5-HT membrane transport and its degradation by monoamine oxidase (MAO) in the mammalian ovary. Using pharmacologic agents and immunohistochemical staining of the cryosections of ovaries after serotonin administration in vitro, we demonstrated the activity of transport and degradation systems in ovarian follicles. The MAO inhibitor pargyline increased serotonin accumulation in the granulosa cells of growing follicles, indicating the activity of both serotonin uptake and degradation by MAO in these cells. The activity of MAO and the specificity of the membrane transport of serotonin was confirmed in primary granulosa cell culture treated with pargyline and fluoxetine. Moreover, the accumulation of serotonin is more effective in the denuded oocytes and occurs at lower concentrations than in the oocytes within the follicles. This confirms that the activity of SERT and MAO in the granulosa cells surrounding the oocytes impedes the accumulation of serotonin in the oocytes and forms a functional barrier to serotonin.
Topics: Animals; Mice; Female; Serotonin; Granulosa Cells; Ovarian Follicle; Oocytes; Monoamine Oxidase; Serotonin Plasma Membrane Transport Proteins; Pargyline; Mammals
PubMed: 36499156
DOI: 10.3390/ijms232314828