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Bicyclic alpha-Iminophosphonates as High Affinity Imidazoline I-2 Receptor Ligands for Alzheimer's Disease

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dc.contributor.authorAbas, Sonia
dc.contributor.authorRodriguez-Arevalo, Sergio
dc.contributor.authorBagan, Andrea
dc.contributor.authorGrinan-Ferre, Christian
dc.contributor.authorVasilopoulou, Foteini
dc.contributor.authorBrocos-Mosquera, Iria
dc.contributor.authorMuguruza, Carolina
dc.contributor.authorPerez, Belen
dc.contributor.authorMolins, Elies
dc.contributor.authorJavier Luque, F
dc.contributor.authorPerez-Lozano, Pilar
dc.contributor.authorde Jonghe, Steven
dc.contributor.authorDaelemans, Dirk
dc.contributor.authorNaesens, Lieve
dc.contributor.authorBrea, Jose
dc.contributor.authorIsabel Loza, M
dc.contributor.authorHernández-Hernández, Elena
dc.contributor.authorGarcia-Sevilla, Jesus A
dc.contributor.authorJulia Garcia-Fuster, M
dc.contributor.authorRadan, Milica
dc.contributor.authorDjikic, Teodora
dc.contributor.authorNikolic, Katarina
dc.contributor.authorPallas, Merce
dc.contributor.authorCallado, Luis F
dc.contributor.authorEscolano, Carmen
dc.date.accessioned2024-09-13T09:11:40Z
dc.date.available2024-09-13T09:11:40Z
dc.date.issued2020-04-09
dc.description.abstractImidazoline I-2 receptors (I-2-IR), widely distributed in the CNS and altered in patients that suffer from neurodegenerative disorders, are orphans from a structural point of view, and new I-2-IR ligands are urgently required for improving their pharmacological characterization. We report the synthesis and three-dimensional quantitative structure-activity relationship (3D-QSAR) studies of a new family of bicyclic alpha-iminophosphonates endowed with relevant affinities for human brain I-2-IR. Acute treatment in mice with a selected compound significantly decreased Fas-associated protein with death domain (FADD) in the hippocampus, a key signaling mediator of neuroprotective actions. Additionally, in vivo studies in the familial Alzheimer's disease 5xFAD murine model revealed beneficial effects in behavior and cognition. These results are supported by changes in molecular pathways related to cognitive decline and Alzheimer's disease. Therefore, bicyclic alpha-iminophosphonates are tools that may open new therapeutic avenues for I-2-IR, particularly for unmet neurodegenerative conditions.en
dc.description.sponsorshipWe strongly acknowledge the advice of Dr. Andres G. Fernandez (our mentor in the CaixaImpulse 2018 program) for invaluable advice. This study was supported by the Ministerio de Economia y Competitividad of Spain (SAF2016-77703) and the Basque Government (IT1211-19). The project leading to these results has received funding from la Caixa Foundation (ID 100010434) under agreement CI18-00002. This activity has received funding from the European Institute of Innovation and Technology (EIT). This body of the European Union receives support from the European Union's Horizon 2020 research and innovation programme. C.G.-F, F.V., C.E., S.R.-A., A.B., and M.P. belong to 2017SGR106 (Generalitat de Catalunya). J.A.G.-S. is a member emeritus of the Institut d'Estudis Catalans. Financial support was provided for F.V. (University of Barcelona, APIF_ 2017), S.R.-A. (Generalitat de Catalunya, 2018FI_B_ 00227), A. B. (Institute of Biomedicine UB_2018), C.M. (Marie Sklodowska-Curie Actions Individual Fellowships H2020-MSCA-IF-2016, ID747487), and E.H.-H. (Consejeria de Innovacion, Investigacion y Turismo del Gobierno de las Islas Baleares y del Fondo Social Europeo, FPI/2102/2018). F.J.L. acknowledges the financial support from the Spanish Ministerio de Economia, Industria y Competitividad (grant MDM-2017-0767; AEI/FEDER UE), and Generalitat de Catalunya (grant 2017SGR1746). M.R., T.D., and K.N. kindly acknowledge Ministry of Science and Technological Development of the Republic of Serbia, Project Contract No. 172033, and HORISON2020-COST-Action CA18133 ERNEST: European Research Network on Signal Transduction.es_ES
dc.format.number7es_ES
dc.format.page3610-3633es_ES
dc.format.volume63es_ES
dc.identifier.citationAbas Sonia, Rodriguez-Arevalo Sergio, Bagan Andrea, Grinan-Ferre Christian, Vasilopoulou Foteini, Brocos-Mosquera Iria, et al. Bicyclic alpha-Iminophosphonates as High Affinity Imidazoline I-2 Receptor Ligands for Alzheimer's Disease. J Med Chem. 2020 Apr 09;63(7):3610-3633. Epub 2020 Mar 19.en
dc.identifier.doi10.1021/acs.jmedchem.9b02080
dc.identifier.e-issn1520-4804es_ES
dc.identifier.issn0022-2623
dc.identifier.journalJournal of Medicinal Chemistryes_ES
dc.identifier.otherhttp://hdl.handle.net/20.500.13003/11009
dc.identifier.pubmedID32150414es_ES
dc.identifier.puiL2005687973
dc.identifier.scopus2-s2.0-85083077827
dc.identifier.urihttps://hdl.handle.net/20.500.12105/22847
dc.identifier.wos526405300015
dc.language.isoengen
dc.publisherAmerican Chemical Society (ACS)
dc.relation.publisherversionhttps://dx.doi.org/10.1021/acs.jmedchem.9b02080en
dc.rights.accessRightsopen accessen
dc.rights.licenseAttribution-NonCommercial-NoDerivatives 4.0 International*
dc.rights.urihttp://creativecommons.org/licenses/by-nc-nd/4.0/*
dc.subject.decsAnimales*
dc.subject.decsImidazoles*
dc.subject.decsNootrópicos*
dc.subject.decsOrganofosfonatos*
dc.subject.decsCélulas de Riñón Canino Madin Darby*
dc.subject.decsReacción de Cicloadición*
dc.subject.decsFemenino*
dc.subject.decsLigandos*
dc.subject.decsPerros*
dc.subject.decsCélulas Vero*
dc.subject.decsCélulas HeLa*
dc.subject.decsReceptores de Imidazolina*
dc.subject.decsRelación Estructura-Actividad Cuantitativa*
dc.subject.decsHumanos*
dc.subject.decsHipocampo*
dc.subject.decsChlorocebus aethiops*
dc.subject.decsEnfermedad de Alzheimer*
dc.subject.decsRatones*
dc.subject.decsEstructura Molecular*
dc.subject.meshAlzheimer Disease*
dc.subject.meshMolecular Structure*
dc.subject.meshOrganophosphonates*
dc.subject.meshQuantitative Structure-Activity Relationship*
dc.subject.meshHippocampus*
dc.subject.meshHumans*
dc.subject.meshVero Cells*
dc.subject.meshChlorocebus aethiops*
dc.subject.meshHeLa Cells*
dc.subject.meshCycloaddition Reaction*
dc.subject.meshMadin Darby Canine Kidney Cells*
dc.subject.meshLigands*
dc.subject.meshDogs*
dc.subject.meshFemale*
dc.subject.meshAnimals*
dc.subject.meshImidazoles*
dc.subject.meshNootropic Agents*
dc.subject.meshImidazoline Receptors*
dc.subject.meshMice*
dc.titleBicyclic alpha-Iminophosphonates as High Affinity Imidazoline I-2 Receptor Ligands for Alzheimer's Diseaseen
dc.typeresearch articleen
dc.type.hasVersionSMURes_ES
dspace.entity.typePublication
relation.isPublisherOfPublication226dc880-a160-4773-8f02-d8d2680f07d3
relation.isPublisherOfPublication.latestForDiscovery226dc880-a160-4773-8f02-d8d2680f07d3

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