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Chemical Biology & Drug Design Aug 2023Eight derivatives of benzyloxy-derived halogenated chalcones (BB1-BB8) were synthesized and tested for their ability to inhibit monoamine oxidases (MAOs). MAO-A was less...
Eight derivatives of benzyloxy-derived halogenated chalcones (BB1-BB8) were synthesized and tested for their ability to inhibit monoamine oxidases (MAOs). MAO-A was less efficiently inhibited by all compounds than MAO-B. Additionally, the majority of the compounds displayed significant MAO-B inhibitory activities at 1 μM with residual activities of less than 50%. With an IC value of 0.062 μM, compound BB4 was the most effective in inhibiting MAO-B, followed by compound BB2 (IC = 0.093 μM). The lead molecules showed good activity than the reference MAO-B inhibitors (Lazabemide IC = 0.11 μM and Pargyline Pargyline IC = 0.14). The high selectivity index (SI) values for MAO-B were observed in compounds BB2 and BB4 (430.108 and 645.161, respectively). Kinetics and reversibility experiments revealed that BB2 and BB4 were reversible competitive MAO-B inhibitors with K values of 0.030 ± 0.014 and 0.011 ± 0.005 μM, respectively. Swiss target prediction confirmed the high probability in the targets of MAO-B for both compounds. Hypothetical binding mode revealed that the BB2 or BB4 is similarly oriented to the binding cavity of MAO-B. Based on the modelling results, BB4 showed a stable confirmation during the dynamic simulation. From these results, it was concluded that BB2 and BB4 were potent selective reversible MAO-B inhibitors and they can be considered drug candidates for treating related neurodegenerative diseases such as Parkinson's disease.
Topics: Monoamine Oxidase Inhibitors; Chalcones; Structure-Activity Relationship; Pargyline; Pharmacophore; Molecular Docking Simulation; Monoamine Oxidase
PubMed: 37011915
DOI: 10.1111/cbdd.14238 -
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 -
Future Medicinal Chemistry Jan 2023Propargylamine is a chemical moiety whose properties have made it a widely distributed group within the fields of medicinal chemistry and chemical biology. Its... (Review)
Review
Propargylamine is a chemical moiety whose properties have made it a widely distributed group within the fields of medicinal chemistry and chemical biology. Its particular reactivity has traditionally popularized the preparation of propargylamine derivatives using a large variety of synthetic strategies, which have facilitated the access to these compounds for the study of their biomedical potential. This review comprehensively covers and analyzes the applications that propargylamine-based derivatives have achieved in the drug discovery field, both from a medicinal chemistry perspective and from a chemical biology-oriented approach. The principal therapeutic fields where propargylamine-based compounds have made an impact are identified, and a discussion of their influence and growing potential is included.
Topics: Pargyline; Drug Discovery; Propylamines
PubMed: 36802855
DOI: 10.4155/fmc-2022-0243 -
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 -
The Journal of Physiological Sciences :... Oct 2022To investigate the roles of the serotonin (5-HT) transporter (SERT) and plasma membrane monoamine transporter (PMAT) in 5-HT uptake and its metabolism in the heart, we...
To investigate the roles of the serotonin (5-HT) transporter (SERT) and plasma membrane monoamine transporter (PMAT) in 5-HT uptake and its metabolism in the heart, we monitored myocardial interstitial levels of 5-HT and 5-HIAA, a metabolite of 5-HT by monoamine oxidase (MAO), in anesthetized rats using a microdialysis technique. Fluoxetine (SERT inhibitor), decynium-22 (PMAT inhibitor), or their mixture was locally administered by reverse-microdialysis for 60 min. Subsequently, pargyline (MAO inhibitor) was co-administered. Fluoxetine rapidly increased dialysate 5-HT concentration, while decynium-22 gradually increased it. The mixture induced a larger increase in dialysate 5-HT concentration compared to fluoxetine or decynium-22 alone. Fluoxetine increased dialysate 5-HIAA concentration, and this increase was abolished by pargyline. Decynium-22 and the mixture did not change dialysate 5-HIAA concentration, which were not affected by pargyline. Both SERT and PMAT regulate myocardial interstitial 5-HT levels by its uptake; however, 5-HT uptake via PMAT leads to 5-HT metabolism by MAO.
Topics: Animals; Rats; Dialysis Solutions; Fluoxetine; Hydroxyindoleacetic Acid; Membrane Transport Proteins; Monoamine Oxidase; Monoamine Oxidase Inhibitors; Pargyline; Serotonin; Heart
PubMed: 36289481
DOI: 10.1186/s12576-022-00852-2 -
Cells Aug 2022Diabetes leads to cardiomyopathy and heart failure, the leading cause of death for diabetic patients. Monoamine oxidase (MAO) inhibition in diabetic cardiomyopathy...
Diabetes leads to cardiomyopathy and heart failure, the leading cause of death for diabetic patients. Monoamine oxidase (MAO) inhibition in diabetic cardiomyopathy prevents oxidative stress, mitochondrial and endoplasmic reticulum stress and the development of diastolic dysfunction. However, it is unclear whether, in addition to the direct effects exerted on the mitochondria, MAO activity is able to post-transcriptionally regulate cardiomyocyte function and survival in diabetes. To this aim, we performed gene and miRNA expression profiling in cardiac tissue from streptozotocin-treated mice (model of type 1 diabetes (T1D)), administered with either vehicle or MAOs inhibitor pargyline for 12 weeks. We found that inhibition of MAO activity in T1D hearts leads to profound transcriptomic changes, affecting autophagy and pro-survival pathways activation. MAO activity in T1D hearts increased miR-133a-3p, -193a-3p and -27a-3p expression. These miRNAs target insulin-like growth factor receptor 1 (), growth factor receptor bound protein 10 and inositol polyphosphate 4 phosphatase type 1A, respectively, all components of the IGF1R/PI3K/AKT signaling pathway. Indeed, AKT activation was significantly downregulated in T1D hearts, whereas MAO inhibition restored the activation of this pro-survival pathway. The present study provides an important link between MAO activity, transcriptomic changes and activation of pro-survival signaling and autophagy in diabetic cardiomyopathy.
Topics: Animals; Diabetes Mellitus, Type 1; Diabetic Cardiomyopathies; Mice; MicroRNAs; Monoamine Oxidase; Phosphatidylinositol 3-Kinases; Proto-Oncogene Proteins c-akt; Reactive Oxygen Species; Signal Transduction
PubMed: 36078109
DOI: 10.3390/cells11172697 -
European Journal of Medicinal Chemistry Nov 2022Monoamine oxidase enzyme is necessary for the management of brain functions. It oxidatively metabolizes monoamines and produces ammonia, aldehyde and hydrogen peroxide... (Review)
Review
Monoamine oxidase enzyme is necessary for the management of brain functions. It oxidatively metabolizes monoamines and produces ammonia, aldehyde and hydrogen peroxide as by-products. Excessive production of by-products of monoamine metabolism generates free radicals which cause cellular apoptosis and several neurodegenerative disorders for example Alzheimer's disease, Parkinson's disease, depression and autism. The inhibition of MAOs is an attractive target for the treatment of neurological disorders. Clinically approved MAO inhibitors for example selegiline, rasagiline, clorgyline, pargyline etc. are irreversible in nature and cause some adverse effects while recently studied reversible MAO inhibitors are devoid of harmful effects of old monoamine oxidase inhibitors. In this review article we have listed various synthesized molecules containing different moieties like coumarin, chalcone, thiazole, thiourea, caffeine, pyrazole, chromone etc. along with their activity, mode of action, structure activity relationship and molecular docking studies.
Topics: Aldehydes; Ammonia; Caffeine; Chalcones; Chromones; Clorgyline; Coumarins; Hydrogen Peroxide; Molecular Docking Simulation; Monoamine Oxidase; Monoamine Oxidase Inhibitors; Pargyline; Pyrazoles; Selegiline; Structure-Activity Relationship; Thiazoles; Thiourea
PubMed: 36037788
DOI: 10.1016/j.ejmech.2022.114655 -
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 -
The Journal of Organic Chemistry May 2022We report a cascaded oxidative sulfonylation of -propargylamine via a three-component coupling reaction using DABCO·(SO) (DABSO). 3-Arylsulfonylquinolines were obtained...
We report a cascaded oxidative sulfonylation of -propargylamine via a three-component coupling reaction using DABCO·(SO) (DABSO). 3-Arylsulfonylquinolines were obtained by mixing diazonium tetrafluoroborate, -propargylamine, and DABSO under argon atmosphere in dichloroethane (DCE) for 1 h. In a radical pathway, DABSO was utilized as the sulfone source and an oxidant in this radical-mediated cascaded reaction.
Topics: Oxidative Stress; Pargyline; Propylamines; Sulfones
PubMed: 35509227
DOI: 10.1021/acs.joc.2c00499