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Martynov A, Farber B, Bomko T, Beckles DL, Kleyn I. Molecular Modeling, Synthesis, and Antihyperglycemic Activity of the New Benzimidazole Derivatives - Imidazoline Receptor Agonists. Drug Des Devel Ther 2024; 18:1035-1052. [PMID: 38585255 PMCID: PMC10999201 DOI: 10.2147/dddt.s447289] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2023] [Accepted: 02/28/2024] [Indexed: 04/09/2024] Open
Abstract
Introduction The paper presents the results of a study on the first synthesized benzimidazole derivatives obtained from labile nature carboxylic acids. The synthesis conditions of these substances were studied, their structure was proved, and some components were found to have sugar-reducing activity on the model of alloxan diabetes in rats. Methods The study used molecular modeling methods such as docking based on the evolutionary model (igemdock), RP_HPLC method to monitor the synthesis reaction, and 1H NMR and 13C NMR, and other methods of organic chemistry to confirm the structures of synthesized substances. Results & Discussion The docking showed that the ursodeoxycholic acid benzimidazole derivatives have high tropics to all imidazoline receptor carriers (PDB ID: 2XCG, 2bk3, 3p0c, 1QH4). The ursodeoxycholic acid benzimidazole derivative and arginine and histidine benzimidazole derivatives showed the highest sugar-lowering activity in the experiment on alloxan-diabetic rats. For these derivatives, the difference in glucose levels of treated rats was significant against untreated control. Therefore, the new derivatives of benzimidazole and labile natural organic acids can be used to create new classes of imidazoline receptor inhibitors for the treatment of diabetes mellitus and hypertension.
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Affiliation(s)
- Artur Martynov
- Laboratory and Clinical department of Molecular Immunopharmacology, SI “ I. Mechnikov Institute of Microbiology and Immunology of National Academy of Medical Sciences of Ukraine, Kharkiv, Ukraine
| | | | - Tatyana Bomko
- Laboratory and Clinical department of Molecular Immunopharmacology, SI “ I. Mechnikov Institute of Microbiology and Immunology of National Academy of Medical Sciences of Ukraine, Kharkiv, Ukraine
| | | | - Ilya Kleyn
- SUNY Downstate Medical Center / University Hospital of Brooklyn, New York, NY, USA
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Abstract
Proper elucidation of drug-target interaction is one of the most significant steps at the early stages of the drug development research. Computer-aided drug design tools have substantial contribution to this stage. In this chapter, we specifically concentrate on the computational methods widely used to develop reversible inhibitors for monoamine oxidase (MAO) isozymes. In this context, current computational techniques in identifying the best drug candidates showing high potency are discussed. The protocols of structure-based drug design methodologies, namely, molecular docking, in silico screening, and molecular dynamics simulations, are presented. Employing case studies of safinamide binding to MAO B, we demonstrate how to use AutoDock 4.2.6 and NAMD software packages.
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Affiliation(s)
- Kemal Yelekçi
- Department of Bioinformatics and Genetics, Faculty of Engineering and Natural Sciences, Kadir Has University, Istanbul, Turkey.
| | - Safiye Sağ Erdem
- Department of Chemistry, Faculty of Arts and Sciences, Marmara University, Istanbul, Turkey
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Carpéné C, Viana P, Fontaine J, Laurell H, Grolleau JL. Multiple Direct Effects of the Dietary Protoalkaloid N-Methyltyramine in Human Adipocytes. Nutrients 2022; 14:nu14153118. [PMID: 35956295 PMCID: PMC9370673 DOI: 10.3390/nu14153118] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2022] [Revised: 07/23/2022] [Accepted: 07/27/2022] [Indexed: 02/06/2023] Open
Abstract
Dietary amines have been the subject of a novel interest in nutrition since the discovery of trace amine-associated receptors (TAARs), especially TAAR-1, which recognizes tyramine, phenethylamine, tryptamine, octopamine, N-methyltyramine (NMT), synephrine, amphetamine and related derivatives. Alongside the psychostimulant properties of TAAR-1 ligands, it is their ephedrine-like action on weight loss that drives their current consumption via dietary supplements advertised for ‘fat-burning’ properties. Among these trace amines, tyramine has recently been described, at high doses, to exhibit an antilipolytic action and activation of glucose transport in human adipocytes, i.e., effects that are facilitating lipid storage rather than mobilization. Because of its close structural similarity to tyramine, NMT actions on human adipocytes therefore must to be reevaluated. To this aim, we studied the lipolytic and antilipolytic properties of NMT together with its interplay with insulin stimulation of glucose transport along with amine oxidase activities in adipose cells obtained from women undergoing abdominal surgery. NMT activated 2-deoxyglucose uptake when incubated with freshly isolated adipocytes at 0.01–1 mM, reaching one-third of the maximal stimulation by insulin. However, when combined with insulin, NMT limited by half the action of the lipogenic hormone on glucose transport. The NMT-induced stimulation of hexose uptake was sensitive to inhibitors of monoamine oxidases (MAO) and of semicarbazide-sensitive amine oxidase (SSAO), as was the case for tyramine and benzylamine. All three amines inhibited isoprenaline-induced lipolysis to a greater extent than insulin, while they were poorly lipolytic on their own. All three amines—but not isoprenaline—interacted with MAO or SSAO. Due to these multiple effects on human adipocytes, NMT cannot be considered as a direct lipolytic agent, potentially able to improve lipid mobilization and fat oxidation in consumers of NMT-containing dietary supplements.
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Affiliation(s)
- Christian Carpéné
- Institut des Maladies Métaboliques et Cardiovasculaires (I2MC), Institut National de la Santé et de la Recherche Médicale (INSERM U1297), I2MC, CEDEX 4, 31432 Toulouse, France; (P.V.); (J.F.); (H.L.)
- CHU Rangueil, Université Paul Sabatier, I2MC, CEDEX 4, 31432 Toulouse, France
- Correspondence:
| | - Pénélope Viana
- Institut des Maladies Métaboliques et Cardiovasculaires (I2MC), Institut National de la Santé et de la Recherche Médicale (INSERM U1297), I2MC, CEDEX 4, 31432 Toulouse, France; (P.V.); (J.F.); (H.L.)
- CHU Rangueil, Université Paul Sabatier, I2MC, CEDEX 4, 31432 Toulouse, France
| | - Jessica Fontaine
- Institut des Maladies Métaboliques et Cardiovasculaires (I2MC), Institut National de la Santé et de la Recherche Médicale (INSERM U1297), I2MC, CEDEX 4, 31432 Toulouse, France; (P.V.); (J.F.); (H.L.)
- CHU Rangueil, Université Paul Sabatier, I2MC, CEDEX 4, 31432 Toulouse, France
| | - Henrik Laurell
- Institut des Maladies Métaboliques et Cardiovasculaires (I2MC), Institut National de la Santé et de la Recherche Médicale (INSERM U1297), I2MC, CEDEX 4, 31432 Toulouse, France; (P.V.); (J.F.); (H.L.)
- CHU Rangueil, Université Paul Sabatier, I2MC, CEDEX 4, 31432 Toulouse, France
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Carpéné C, Marti L, Morin N. Increased monoamine oxidase activity and imidazoline binding sites in insulin-resistant adipocytes from obese Zucker rats. World J Biol Chem 2022; 13:15-34. [PMID: 35126867 PMCID: PMC8790288 DOI: 10.4331/wjbc.v13.i1.15] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/26/2021] [Revised: 07/09/2021] [Accepted: 01/14/2022] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Despite overt insulin resistance, adipocytes of genetically obese Zucker rats accumulate the excess of calorie intake in the form of lipids.
AIM To investigate whether factors can replace or reinforce insulin lipogenic action by exploring glucose uptake activation by hydrogen peroxide, since it is produced by monoamine oxidase (MAO) and semicarbazide-sensitive amine oxidase (SSAO) in adipocytes.
METHODS 3H-2-deoxyglucose uptake (2-DG) was determined in adipocytes from obese and lean rats in response to insulin or MAO and SSAO substrates such as tyramine and benzylamine. 14C-tyramine oxidation and binding of imidazolinic radioligands [3H-Idazoxan, 3H-(2-benzofuranyl)-2-imidazoline] were studied in adipocytes, the liver, and muscle. The influence of in vivo administration of tyramine + vanadium on glucose handling was assessed in lean and obese rats.
RESULTS 2-DG uptake and lipogenesis stimulation by insulin were dampened in adipocytes from obese rats, when compared to their lean littermates. Tyramine and benzylamine activation of hexose uptake was vanadate-dependent and was also limited, while MAO was increased and SSAO decreased. These changes were adipocyte-specific and accompanied by a greater number of imidazoline I2 binding sites in the obese rat, when compared to the lean. In vitro, tyramine precluded the binding to I2 sites, while in vivo, its administration together with vanadium lowered fasting plasma levels of glucose and triacylglycerols in obese rats.
CONCLUSION The adipocytes from obese Zucker rats exhibit increased MAO activity and imidazoline binding site number. However, probably as a consequence of SSAO down-regulation, the glucose transport stimulation by tyramine is decreased as much as that of insulin in these insulin-resistant adipocytes. The adipocyte amine oxidases deserve more studies with respect to their putative contribution to the management of glucose and lipid handling.
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Affiliation(s)
- Christian Carpéné
- Institut des Maladies Métaboliques et Cardiovasculaires, INSERM, Toulouse 31342, France
| | - Luc Marti
- Institut des Maladies Métaboliques et Cardiovasculaires, INSERM, Toulouse 31342, France
| | - Nathalie Morin
- Institut des Maladies Métaboliques et Cardiovasculaires, INSERM, Toulouse 31342, France
- Faculté de Pharmacie de Paris, Paris University, Paris 75270, France
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High doses of tyramine stimulate glucose transport in human fat cells. J Physiol Biochem 2022; 78:543-556. [DOI: 10.1007/s13105-021-00864-3] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/25/2021] [Accepted: 12/09/2021] [Indexed: 01/13/2023]
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Shetnev A, Osipyan A, Baykov S, Sapegin A, Chirkova Z, Korsakov M, Petzer A, Engelbrecht I, Petzer JP. Novel monoamine oxidase inhibitors based on the privileged 2-imidazoline molecular framework. Bioorg Med Chem Lett 2018; 29:40-46. [PMID: 30455149 DOI: 10.1016/j.bmcl.2018.11.018] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/17/2018] [Revised: 11/06/2018] [Accepted: 11/08/2018] [Indexed: 12/22/2022]
Abstract
Series of structurally diverse 2-imidazoline derivatives have been synthesized by condensation of substituted aldehydes with ethylenediamine, Pd-catalyzed N-arylation of 2-imidazolines and by the formation of 1,2,4-oxadiazoles and benzoxazepines from 2-imidazoline-containing precursors. The 2-imidazoline derivatives were evaluated as potential inhibitors of human monoamine oxidase (MAO) A and B. Among the 2-imidazolines, good potency inhibitors were discovered with compound 9p (IC50 = 0.012 µM) being the most potent MAO-B inhibitor, while compound 9d (IC50 = 0.751 µM) was the most potent MAO-A inhibitor of the series. These potencies are in the same range as those of reference MAO inhibitors used in the clinic. Among 33 compounds evaluated, 13 exhibited IC50 values in the submicromolar range for the inhibition of an MAO isoform. It is postulated that the imidazoline moieties of some of these inhibitors may be recognized by the imidazoline I2-binding site of MAO. Good potency MAO inhibitors may be useful for the treatment of neuropsychiatric and neurodegenerative disorders such as depression and Parkinson's disease, and future application for the treatment of prostate cancer, congestive heart failure and Alzheimer's disease. In addition, high potency 2-imidazoline-derived MAO inhibitors may be used as potential probes for the imidazoline binding sites of the MAOs, as well as to determine alternative binding regions of imidazoline within the MAO active site.
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Affiliation(s)
- Anton Shetnev
- Pharmaceutical Technology Transfer Center, Ushinsky Yaroslavl State Pedagogical University, 108 Respublikanskaya St., Yaroslavl 150000, Russian Federation.
| | - Angelina Osipyan
- Institute of Chemistry, Saint Petersburg State University, 26 Universitetskii Prospect, Peterhof, Saint Petersburg 198504, Russian Federation.
| | - Sergey Baykov
- Institute of Chemistry, Saint Petersburg State University, 26 Universitetskii Prospect, Peterhof, Saint Petersburg 198504, Russian Federation.
| | - Alexander Sapegin
- Institute of Chemistry, Saint Petersburg State University, 26 Universitetskii Prospect, Peterhof, Saint Petersburg 198504, Russian Federation.
| | - Zhanna Chirkova
- Yaroslavl State Technical University, 150023 Yaroslavl, Russian Federation.
| | - Michail Korsakov
- Pharmaceutical Technology Transfer Center, Ushinsky Yaroslavl State Pedagogical University, 108 Respublikanskaya St., Yaroslavl 150000, Russian Federation.
| | - Anél Petzer
- Pharmaceutical Chemistry and Centre of Excellence for Pharmaceutical Sciences, North-West University, Potchefstroom 2520, South Africa.
| | - Idalet Engelbrecht
- Pharmaceutical Chemistry and Centre of Excellence for Pharmaceutical Sciences, North-West University, Potchefstroom 2520, South Africa.
| | - Jacobus P Petzer
- Pharmaceutical Chemistry and Centre of Excellence for Pharmaceutical Sciences, North-West University, Potchefstroom 2520, South Africa.
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Tolerance and cross-tolerance to the antinociceptive effects of oxycodone and the imidazoline I 2 receptor agonist phenyzoline in adult male rats. Psychopharmacology (Berl) 2017; 234:1871-1880. [PMID: 28314949 PMCID: PMC5451304 DOI: 10.1007/s00213-017-4599-4] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/03/2016] [Accepted: 03/08/2017] [Indexed: 10/19/2022]
Abstract
RATIONALE Emerging evidence suggests the potential utility of combining opioids with imidazoline I2 receptor agonists for chronic pain. However, chronic pain management requires prolonged pharmacotherapy, and the consequence of such combination therapy remains unclear. OBJECTIVE This study examined the anti-hyperalgesic effect of the opioid oxycodone, the selective I2 receptor agonist phenyzoline, alone and in combination, during prolonged treatment. METHODS Von Frey filament test was used to examine the anti-hyperalgesic effect of drugs in complete Freund's adjuvant (CFA)-induced inflammatory pain or chronic constriction injury (CCI)-induced neuropathic pain in rats. Twice-daily treatment with oxycodone and phenyzoline, alone or in combination, was continued until the development of significant tolerance (oxycodone) or as long as 19 days passed (phenyzoline). RESULTS In rats receiving CFA or CCI manipulation, mechanical hyperalgesia was dose-dependently reversed by oxycodone and phenyzoline. Twice-daily treatment with 2 × ED50 dose of oxycodone for 7 days led to significant antinociceptive tolerance to oxycodone but not cross-tolerance to phenyzoline. Similarly, twice-daily treatment with 2 × ED50 dose of phenyzoline for 19 days led to significant antinociceptive tolerance to phenyzoline but not cross-tolerance to oxycodone. Twice-daily treatment with the combined oxycodone and phenyzoline using different ratios (1:3, 1:1 and 3: 1) at the doses that were functionally equivalent to the treatment doses of oxycodone and phenyzoline for 13-19 days generally led to delayed antinociceptive tolerance. CONCLUSIONS Combination therapy with oxycodone and I2 receptor agonists maintains prolonged antinociceptive effectiveness with reduced propensity to develop tolerance.
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Ramsay RR. Molecular aspects of monoamine oxidase B. Prog Neuropsychopharmacol Biol Psychiatry 2016; 69:81-9. [PMID: 26891670 DOI: 10.1016/j.pnpbp.2016.02.005] [Citation(s) in RCA: 68] [Impact Index Per Article: 7.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/27/2015] [Revised: 02/06/2016] [Accepted: 02/11/2016] [Indexed: 02/07/2023]
Abstract
Monoamine oxidases (MAO) influence the monoamine levels in brain by virtue of their role in neurotransmitter breakdown. MAO B is the predominant form in glial cells and in platelets. MAO B structure, function and kinetics are described as a background for the effect of alterations in its activity on behavior. The need to inhibit MAO B to combat decreased brain amines continues to drive the search for new drugs. Reversible and irreversible inhibitors are now designed using data-mining, computational screening, docking and molecular dynamics. Multi-target ligands designed to combat the elevated activity of MAO B in Alzheimer's and Parkinson's Diseases incorporate MAO inhibition (usually irreversible) as well as iron chelation, antioxidant or neuroprotective properties. The main focus of drug design is the catalytic activity of MAO, but the imidazoline I2 site in the entrance cavity of MAO B is also a pharmacological target. Endogenous regulation of MAO B expression is discussed briefly in light of new studies measuring mRNA, protein, or activity in healthy and degenerative samples, including the effect of DNA methylation on the expression. Overall, this review focuses on examples of recent research on the molecular aspects of the expression, activity, and inhibition of MAO B.
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Affiliation(s)
- Rona R Ramsay
- Biomedical Sciences Research Complex, University of St Andrews, North Haugh, St Andrews KY16 9ST, United Kingdom.
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( E )-3-Heteroarylidenechroman-4-ones as potent and selective monoamine oxidase-B inhibitors. Eur J Med Chem 2016; 117:292-300. [DOI: 10.1016/j.ejmech.2016.03.081] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2015] [Revised: 03/23/2016] [Accepted: 03/26/2016] [Indexed: 01/05/2023]
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Butini S, Nikolic K, Kassel S, Brückmann H, Filipic S, Agbaba D, Gemma S, Brogi S, Brindisi M, Campiani G, Stark H. Polypharmacology of dopamine receptor ligands. Prog Neurobiol 2016; 142:68-103. [PMID: 27234980 DOI: 10.1016/j.pneurobio.2016.03.011] [Citation(s) in RCA: 52] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/26/2015] [Revised: 01/26/2016] [Accepted: 03/15/2016] [Indexed: 01/11/2023]
Abstract
Most neurological diseases have a multifactorial nature and the number of molecular mechanisms discovered as underpinning these diseases is continuously evolving. The old concept of developing selective agents for a single target does not fit with the medical need of most neurological diseases. The development of designed multiple ligands holds great promises and appears as the next step in drug development for the treatment of these multifactorial diseases. Dopamine and its five receptor subtypes are intimately involved in numerous neurological disorders. Dopamine receptor ligands display a high degree of cross interactions with many other targets including G-protein coupled receptors, transporters, enzymes and ion channels. For brain disorders like Parkinsońs disease, schizophrenia and depression the dopaminergic system, being intertwined with many other signaling systems, plays a key role in pathogenesis and therapy. The concept of designed multiple ligands and polypharmacology, which perfectly meets the therapeutic needs for these brain disorders, is herein discussed as a general ligand-based concept while focusing on dopaminergic agents and receptor subtypes in particular.
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Affiliation(s)
- S Butini
- Department of Biotechnology, Chemistry and Pharmacy, European Research Centre for Drug Discovery and Development, University of Siena, Via Aldo Moro 2, 53100 Siena, Italy
| | - K Nikolic
- Department of Pharmaceutical Chemistry, Faculty of Pharmacy, University of Belgrade, Vojvode Stepe 450, 11000 Belgrade, Serbia
| | - S Kassel
- Heinrich Heine University Duesseldorf, Institute of Pharmaceutical and Medicinal Chemistry, Universitaetsstr. 1, 40225 Duesseldorf, Germany
| | - H Brückmann
- Heinrich Heine University Duesseldorf, Institute of Pharmaceutical and Medicinal Chemistry, Universitaetsstr. 1, 40225 Duesseldorf, Germany
| | - S Filipic
- Department of Pharmaceutical Chemistry, Faculty of Pharmacy, University of Belgrade, Vojvode Stepe 450, 11000 Belgrade, Serbia
| | - D Agbaba
- Department of Pharmaceutical Chemistry, Faculty of Pharmacy, University of Belgrade, Vojvode Stepe 450, 11000 Belgrade, Serbia
| | - S Gemma
- Department of Biotechnology, Chemistry and Pharmacy, European Research Centre for Drug Discovery and Development, University of Siena, Via Aldo Moro 2, 53100 Siena, Italy
| | - S Brogi
- Department of Biotechnology, Chemistry and Pharmacy, European Research Centre for Drug Discovery and Development, University of Siena, Via Aldo Moro 2, 53100 Siena, Italy
| | - M Brindisi
- Department of Biotechnology, Chemistry and Pharmacy, European Research Centre for Drug Discovery and Development, University of Siena, Via Aldo Moro 2, 53100 Siena, Italy
| | - G Campiani
- Department of Biotechnology, Chemistry and Pharmacy, European Research Centre for Drug Discovery and Development, University of Siena, Via Aldo Moro 2, 53100 Siena, Italy
| | - H Stark
- Heinrich Heine University Duesseldorf, Institute of Pharmaceutical and Medicinal Chemistry, Universitaetsstr. 1, 40225 Duesseldorf, Germany.
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Neuroprotective effects of the monoamine oxidase inhibitor tranylcypromine and its amide derivatives against Aβ(1-42)-induced toxicity. Eur J Pharmacol 2015; 764:256-263. [PMID: 26162702 DOI: 10.1016/j.ejphar.2015.07.015] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2015] [Revised: 07/04/2015] [Accepted: 07/06/2015] [Indexed: 11/21/2022]
Abstract
Monoamine oxidase (MAO) enzymes play a central role in the pathogenesis of Alzheimer's disease (AD) and MAO inhibitors (MAOIs) are antidepressant drugs currently studied for their neuroprotective properties in neurodegenerative disorders. In the present work MAOIs such as tranylcypromine [trans-(+)-2-phenylcyclopropanamine, TCP] and its amide derivatives, TCP butyramide (TCP-But) and TCP acetamide (TCP-Ac), were tested for their ability to protect cortical neurons challenged with synthetic amyloid-β (Aβ)-(1-42) oligomers (100 nM) for 48 h. TCP significantly prevented Aβ-induced neuronal death in a concentration-dependent fashion and was maximally protective only at 10 µM. TCP-But was maximally protective in mixed neuronal cultures at 1 µM, a lower concentration compared to TCP, whereas the new derivative, TCP-Ac, was more efficacious than TCP and TCP-But and significantly protected cortical neurons against Aβ toxicity at nanomolar concentrations (100 nM). Experiments carried out with the Thioflavin-T (Th-T) fluorescence assay for fibril formation showed that TCP and its amide derivatives influenced the early events of the Aβ aggregation process in a concentration-dependent manner. TCP-Ac was more effective than TCP-But and TCP in slowing down the Aβ(1-42) aggregates formation through a lengthening at the lag phase. In our experimental model co-incubation of Aβ(1-42) oligomers with TCP-Ac was able to almost completely prevent Aβ-induced neurodegeneration. These results suggest that inhibition of Aβ oligomer-mediated aggregation significantly contributes to the overall neuroprotective activity of TCP-Ac and also raise the possibility that TCP, and in particular the new compound TCP-Ac, might represent new pharmacological tools to yield neuroprotection in AD.
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Abstract
Accumulating evidence shows a relationship between the human MAO-B (hMAO-B) enzyme and neuropsychiatric/degenerative disorder, personality traits, type II alcoholism, borderline personality disorders, aggressiveness and violence in crime, obsessive-compulsive disorder, depression, suicide, schizophrenia, anorexia nervosa, migraine, dementia, and PD. Thus, MAO-B represents an attractive target for the treatment of a number of human diseases. The discovery, development, and therapeutic use of drugs that inhibit MAO-B are major challenges for future therapy. Various compounds and drugs that selectively target this isoform have been discovered recently. These agents are synthetic compounds or natural products and their analogues, including chalcones, pyrazoles, chromones, coumarins, xanthines, isatin derivatives, thiazolidindiones, (thiazol-2-yl)hydrazones, and analogues of marketed drugs. Despite considerable efforts in understanding the binding interaction with specific substrates or inhibitors, structural information available for the rational design of new hMAO-B inhibitors remains unsatisfactory. Therefore, the quest for novel, potent, and selective hMAO-B inhibitors remains of high interest.
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Affiliation(s)
- Simone Carradori
- Dipartimento Chimica e Tecnologie del Farmaco, Istituto Pasteur-Fondazione Cenci Bolognetti, Sapienza Università di Roma , Piazzale Aldo Moro 5, I-00185 Roma, Italy
| | - Romano Silvestri
- Dipartimento Chimica e Tecnologie del Farmaco, Istituto Pasteur-Fondazione Cenci Bolognetti, Sapienza Università di Roma , Piazzale Aldo Moro 5, I-00185 Roma, Italy
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Malcomson T, Yelekci K, Borrello MT, Ganesan A, Semina E, De Kimpe N, Mangelinckx S, Ramsay RR. cis-cyclopropylamines as mechanism-based inhibitors of monoamine oxidases. FEBS J 2015; 282:3190-8. [DOI: 10.1111/febs.13260] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2014] [Revised: 02/27/2015] [Accepted: 03/06/2015] [Indexed: 11/29/2022]
Affiliation(s)
- Thomas Malcomson
- Biomedical Sciences Research Complex; University of St Andrews; UK
| | - Kemal Yelekci
- Department of Bioinformatics and Genetics; Kadir Has University; Istanbul Turkey
| | | | - A. Ganesan
- School of Pharmacy; University of East Anglia; Norwich UK
| | - Elena Semina
- Department of Sustainable Organic Chemistry and Technology; Ghent University; Belgium
| | - Norbert De Kimpe
- Department of Sustainable Organic Chemistry and Technology; Ghent University; Belgium
| | - Sven Mangelinckx
- Department of Sustainable Organic Chemistry and Technology; Ghent University; Belgium
| | - Rona R. Ramsay
- Biomedical Sciences Research Complex; University of St Andrews; UK
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