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4 results on '"Adeline Giganti"'

1. Characterization of the various functional pathways elicited by synthetic agonists or antagonists at the melatonin MT1 and MT2 receptors

Author

Céline Legros, Clémence Dupré, Chantal Brasseur, Anne Bonnaud, Olivier Bruno, Damien Valour, Preety Shabajee, Adeline Giganti, Olivier Nosjean, Terrence P. Kenakin, and Jean A. Boutin

Subjects
biased ligands, melatonin, melatonin receptors, signaling pathways, Therapeutics. Pharmacology, RM1-950
Abstract

Abstract Melatonin is a neurohormone that translates the circadian rhythm to the peripheral organs through a series of binding sites identified as G protein‐coupled receptors MT1 and MT2. Due to minute amounts of receptor proteins in target organs, the main tool of studies of the melatoninergic system is recombinant expression of the receptors in cellular hosts. Although a number of studies exist on these receptors, studies of several signaling pathways using a large number of melatoninergic compounds are rather limited. We chose to fill this gap to better describe a panel of compounds that have been only partially characterized in terms of functionality. First, we characterized HEK cells expressing MT1 or MT2, and several signaling routes with melatonin itself to validate the approach: GTPγS, cAMP production, internalization, β‐arrestin recruitment, and cell morphology changes (CellKey®). Second, we chose 21 compounds from our large melatoninergic chemical library and characterized them using this panel of signaling pathways. Notably, antagonists were infrequent, and their functionality depended largely on the pathway studied. This will permit redefining the availability of molecular tools that can be used to better understand the in situ activity and roles of these receptors.

Published
2020
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2. Characterization of the various functional pathways elicited by synthetic agonists or antagonists at the melatonin MT1 and MT2 receptors

Author

Preety Shabajee, Olivier Nosjean, Clémence Dupré, Céline Legros, Adeline Giganti, Chantal Brasseur, Olivier Bruno, Jean A. Boutin, Anne Bonnaud, Terrence Peter Kenakin, and Damien Valour

Subjects
biased ligands, media_common.quotation_subject, melatonin, RM1-950, Cell morphology, 030226 pharmacology & pharmacy, Chemical library, Melatonin, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, medicine, melatonin receptors, General Pharmacology, Toxicology and Pharmaceutics, Binding site, Receptor, Internalization, media_common, Chemistry, HEK 293 cells, signaling pathways, Cell biology, Neurology, 030220 oncology & carcinogenesis, Therapeutics. Pharmacology, Signal transduction, medicine.drug
Abstract

Melatonin is a neurohormone that translates the circadian rhythm to the peripheral organs through a series of binding sites identified as G protein‐coupled receptors MT1 and MT2. Due to minute amounts of receptor proteins in target organs, the main tool of studies of the melatoninergic system is recombinant expression of the receptors in cellular hosts. Although a number of studies exist on these receptors, studies of several signaling pathways using a large number of melatoninergic compounds are rather limited. We chose to fill this gap to better describe a panel of compounds that have been only partially characterized in terms of functionality. First, we characterized HEK cells expressing MT1 or MT2, and several signaling routes with melatonin itself to validate the approach: GTPγS, cAMP production, internalization, β‐arrestin recruitment, and cell morphology changes (CellKey®). Second, we chose 21 compounds from our large melatoninergic chemical library and characterized them using this panel of signaling pathways. Notably, antagonists were infrequent, and their functionality depended largely on the pathway studied. This will permit redefining the availability of molecular tools that can be used to better understand the in situ activity and roles of these receptors.

Published
2020

3. S29434, a Quinone Reductase 2 Inhibitor: Main Biochemical and Cellular Characterization

Author

Aakash Patel, Hala Guedouari, Elzbieta Janda, Karine Reybier, Istvan Gacsalyi, Vishalgiri Goswami, Jean A. Boutin, Adeline Giganti, Mathias Antoine, Monivan Chhour, Marie-Claude Viaud-Massuard, Hervé Da Costa, Marc Bertrand, Pierre Ducrot, Jérôme Paysant, Patrick P. Michel, Gilles Ferry, Thierry Le Diguarher, Daniel A. Kane, Françoise Nepveu, Frédéric Bouillaud, Karen Brebner, Gérald Guillaumet, Etienne C. Hirsch, Philippe Dupuis, Johann Stojko, Institut de Recherches SERVIER (IRS), Institut Cochin (IC UM3 (UMR 8104 / U1016)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Paris (UP), Università degli Studi 'Magna Graecia' di Catanzaro [Catanzaro, Italie] (UMG), Egis Pharmaceuticals, Institut de Chimie Organique et Analytique (ICOA), Université d'Orléans (UO)-Centre National de la Recherche Scientifique (CNRS)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut de Chimie du CNRS (INC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut du Cerveau et de la Moëlle Epinière = Brain and Spine Institute (ICM), Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), St. Francis Xavier University (StFX), Pharmacochimie et Biologie pour le Développement (PHARMA-DEV), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut de Chimie de Toulouse (ICT-FR 2599), Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Institut de Chimie du CNRS (INC)-Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD)-Institut de Chimie du CNRS (INC)-Institut de Recherche pour le Développement (IRD), Eurofins-Cerep, Technologie Servier, GICC UMR 7292 CNRS, IMT (Innovation moléculaire et thérapeutique) (IMT), Génétique, immunothérapie, chimie et cancer (GICC), UMR 7292 CNRS [2012-2017] (GICC UMR 7292 CNRS), Université de Tours-Centre National de la Recherche Scientifique (CNRS)-Université de Tours-Centre National de la Recherche Scientifique (CNRS), Oxygen Healthcare Pvt Ltd, Institut de Recherches Internationales Servier [Suresnes] (IRIS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Università degli Studi 'Magna Graecia' di Catanzaro = University of Catanzaro (UMG), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université d'Orléans (UO)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Institut du Cerveau = Paris Brain Institute (ICM), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Institut de Recherche pour le Développement (IRD)-Institut de Chimie de Toulouse (ICT), Institut de Recherche pour le Développement (IRD)-Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Institut National Polytechnique (Toulouse) (Toulouse INP), Université de Toulouse (UT)-Institut de Recherche pour le Développement (IRD)-Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT), GICC EA 7501, IMT (Innovation moléculaire et thérapeutique) (IMT), Groupe innovation et ciblage cellulaire (GICC), EA 7501 [2018-...] (GICC EA 7501), Université de Tours (UT)-Université de Tours (UT), Hirsch, Etienne, Institut de Recherche pour le Développement (IRD)-Institut de Chimie de Toulouse (ICT-FR 2599), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Institut de Recherche pour le Développement (IRD)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées, Université Fédérale Toulouse Midi-Pyrénées-Institut de Chimie du CNRS (INC), and Université de Tours (UT)-Centre National de la Recherche Scientifique (CNRS)-Université de Tours (UT)-Centre National de la Recherche Scientifique (CNRS)

Subjects
0301 basic medicine, Male, Rats Wistar, Pyridines, [SDV]Life Sciences [q-bio], Quinone Reductases / antagonists & inhibitors, Reductase, Cell Membrane / drug effects, 03 medical and health sciences, Mice, 0302 clinical medicine, Pyrrolizidine Alkaloids / pharmacology, In vivo, Cell Line, Tumor, NAD(P)H Dehydrogenase (Quinone), [SDV.BBM] Life Sciences [q-bio]/Biochemistry, Molecular Biology, medicine, Animals, Humans, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, Quinone Reductases, Rats, Wistar, NAD(P)H Dehydrogenase (Quinone) / metabolism, Pyrrolizidine Alkaloids, Pharmacology, chemistry.chemical_classification, Reactive oxygen species, Chemistry, Cell Membrane, Autophagy, Neurodegeneration, Reactive Oxygen Species / metabolism, Hep G2 Cells, Cell Membrane / metabolism, medicine.disease, Quinone, Cell Line / Tumor, Rats, [SDV] Life Sciences [q-bio], 030104 developmental biology, Enzyme, Biochemistry, Molecular Medicine, NAD+ kinase, Reactive Oxygen Species, 030217 neurology & neurosurgery, Pyridines / pharmacology
Abstract

International audience; Quinone reductase 2 (QR2, E.C. 1.10.5.1) is an enzyme with a feature that has attracted attention for several decades: in standard conditions, instead of recognizing NAD(P)H as an electron donor, it recognizes putative metabolites of NADH, such as N-methyl- and N-ribosyl-dihydronicotinamide. QR2 has been particularly associated with reactive oxygen species and memory, strongly suggesting a link among QR2 (as a possible key element in pro-oxidation), autophagy, and neurodegeneration. In molecular and cellular pharmacology, understanding physiopathological associations can be difficult because of a lack of specific and powerful tools. Here, we present a thorough description of the potent, nanomolar inhibitor [2-(2-methoxy-5H-1,4b,9-triaza(indeno[2,1-a]inden-10-yl)ethyl]-2-furamide (S29434 or NMDPEF; IC50 = 5-16 nM) of QR2 at different organizational levels. We provide full detailed syntheses, describe its cocrystallization with and behavior at QR2 on a millisecond timeline, show that it penetrates cell membranes and inhibits QR2-mediated reactive oxygen species (ROS) production within the 100 nM range, and describe its actions in several in vivo models and lack of actions in various ROS-producing systems. The inhibitor is fairly stable in vivo, penetrates cells, specifically inhibits QR2, and shows activities that suggest a key role for this enzyme in different pathologic conditions, including neurodegenerative diseases.

Published
2019
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4. Assessments of cellular melatonin receptor signaling pathways: β-arrestin recruitment, receptor internalization, and impedance variations

Author

Céline Legros, Olivier Bruno, Clémence Dupré, Olivier Nosjean, Jean A. Boutin, Anne Bonnaud, and Adeline Giganti

Subjects
0301 basic medicine, Agonist, medicine.drug_class, Receptors, Melatonin, CHO Cells, Pharmacology, Biology, Partial agonist, Melatonin receptor, Melatonin, 03 medical and health sciences, 0302 clinical medicine, Cricetulus, Cricetinae, medicine, Arrestin, Electric Impedance, Animals, Humans, Receptor, Cell Shape, beta-Arrestins, Cell biology, Protein Transport, 030104 developmental biology, Signal transduction, Luzindole, 030217 neurology & neurosurgery, medicine.drug, Signal Transduction
Abstract

Melatonin receptors belong to the family of G-protein coupled receptors. Agonist-induced receptor activation is terminated with the recruitment of β-arrestin, which leads to receptor internalization. Furthermore, agonist binding induces a shift in cellular shape that translates into a change in the electric impedance of the cell. In the present study, we employed engineered cells to study these internalization-related processes in the context of the two melatonin receptors, MT1 and MT2. To assess these three receptor internalization-related functions and validate the results, we employed four classical ligands of melatonin receptors: the natural agonist melatonin; the super-agonist 2-iodo-melatonin and the two antagonists luzindole and 4-phenyl-2-propionamidotetralin. The assessments confirmed the nature of the agonistic ligands but showed that 4-phenyl-2-propionamidotetralin, a described antagonist, is a biased partial agonist at MT2 with poorer affinity for MT1. The methods are now available to be applied to any receptor system for which multiple signaling pathways must be evaluated for new molecules.

Published
2017

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