Design and validation of the first cell-impermeant melatonin receptor agonist

Autor: Gbahou, Florence, Cecon, Erika, Viault, Guillaume, Gerbier, Romain, Jean-Alphonse, Frédéric, Karamitri, Angeliki, Guillaumet, Gérald, Delagrange, Philippe, Friedlander, Robert, Vilardaga, Jean-Pierre, Suzenet, Franck, Jockers, Ralf
Přispěvatelé: Centre de Psychiatrie et Neurosciences (U894), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut Cochin (IC UM3 (UMR 8104 / U1016)), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut de Chimie Organique et Analytique (ICOA), 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), Neuropeptides centraux et régulations hydrique et cardiovasculaire, Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre interdisciplinaire de recherche en biologie (CIRB), Labex MemoLife, École normale supérieure - Paris (ENS-PSL), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Collège de France (CdF (institution))-Ecole Superieure de Physique et de Chimie Industrielles de la Ville de Paris (ESPCI Paris), Université Paris sciences et lettres (PSL)-École normale supérieure - Paris (ENS-PSL), Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Labex MemoLife, Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), University of Pittsburgh School of Medicine, Pennsylvania Commonwealth System of Higher Education (PCSHE), Unité de Recherches et Découvertes en Neurosciences, Institut de Recherches Servier, University of Pittsburgh (PITT), 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 Cochin (UMR_S567 / UMR 8104), Institut de psychiatrie et neurosciences (U894 / UMS 1266), Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Substances d'Origine Naturelle et Analogues Structuraux (SONAS), Université d'Angers (UA), INSERM U691 - Collège de France, 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), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université d'Orléans (UO)-Institut de Chimie du CNRS (INC)
Jazyk: angličtina
Rok vydání: 2017
Předmět:
Zdroj: British Journal of Pharmacology
British Journal of Pharmacology, 2017, 174 (14), pp.2409-2421. ⟨10.1111/bph.13856⟩
British Journal of Pharmacology, Wiley, 2017, 174 (14), pp.2409-2421. ⟨10.1111/bph.13856⟩
ISSN: 0007-1188
1476-5381
DOI: 10.1111/bph.13856⟩
Popis: International audience; BACKGROUND AND PURPOSEThe paradigm that GPCRs are able to prolong or initiate cellular signalling through intracellular receptors recently emerged. Melatonin binds to G protein-coupled MT1 and MT2 receptors. In contrast to most other hormones targeting GPCRs, melatonin and its synthetic analogues are amphiphilic molecules easily penetrating into cells, but the existence of intracellular receptors is still unclear mainly due to a lack of appropriate tools.EXPERIMENTAL APPROACHWe therefore designed and synthesized a series of hydrophilic melatonin receptor ligands coupled to the Cy3 cyanin fluorophore to reliably monitor its inability to penetrate cells. Two compounds, one lipophilic and one hydrophilic, were then functionally characterized in terms of their affinity for human and murine melatonin receptors expressed in HEK293 cells and their signalling efficacy.KEY RESULTSAmong the different ligands, ICOA-13 showed the desired properties as it was cell-impermeant and bound to human and mouse MT1 and MT2 receptors. ICOA-13 showed differential activities on melatonin receptors ranging from partial to full agonistic properties for the Gi/cAMP and ERK pathway and beta-arrestin 2 recruitment. Notably, ICOA-13 enabled us to discriminate between Gi/cAMP signalling of the MT1 receptor initiated at the cell surface and neuronal mitochondria.CONCLUSIONS AND IMPLICATIONSWe report here the first cell-impermeant melatonin receptor agonist, ICOA-13, which allows us to discriminate between signalling events initiated at the cell surface and intracellular compartments. Detection of mitochondrial MT1 receptors may have an important impact on the development of novel melatonin receptor ligands relevant for neurodegenerative diseases, such as Huntington disease.
Databáze: OpenAIRE
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