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dc.contributor.authorEspadinha, Margarida-
dc.contributor.authorViejo, L.-
dc.contributor.authorLopes, R. M. R. M.-
dc.contributor.authorHerrera-Arozamena, Clara-
dc.contributor.authorMolins, E.-
dc.contributor.authordos Santos, D. J. V. A.-
dc.contributor.authorGonçalves, Lídia M.-
dc.contributor.authorRodríguez-Franco, María Isabel-
dc.contributor.authorRíos, C. d. l.-
dc.contributor.authorSantos, Maria M. M.-
dc.date.accessioned2020-09-04T09:40:13Z-
dc.date.available2020-09-04T09:40:13Z-
dc.date.issued2020-
dc.identifierdoi: 10.1016/j.ejmech.2020.112242-
dc.identifierissn: 1768-3254-
dc.identifier.citationEuropean Journal of Medicinal Chemistry 194 (2020)-
dc.identifier.urihttp://hdl.handle.net/10261/219127-
dc.description.abstractN-Methyl-D-aspartate receptors (NMDARs) are crucial for the normal function of the central nervous system (CNS), and fundamental in memory and learning-related processes. The overactivation of these receptors is associated with numerous neurodegenerative and psychiatric disorders. Therefore, NMDAR is considered a relevant therapeutic target for many CNS disorders. Herein, we report the synthesis and pharmacological evaluation of a new scaffold with antagonistic activity for NMDAR. Specifically, a chemical library of eighteen 1-aminoindan-2-ol tetracyclic lactams was synthesized and screened as NMDAR antagonists. The compounds were obtained by chiral pool synthesis using enantiomerically pure 1-aminoindan-2-ols as chiral inductors, and their stereochemistry was proven by X-ray crystallographic analysis of two target compounds. Most compounds reveal NMDAR antagonism, and eleven compounds display IC values in a Ca entry-sensitive fluo-4 assay in the same order of magnitude of memantine, a clinically approved NMDAR antagonist. Docking studies suggest that the novel compounds can act as NMDAR channel blockers since there is a compatible conformation with MK-801 co-crystallized with NMDAR channel. In addition, we show that the tetracyclic 1-aminoindan-2-ol derivatives are brain permeable and non-toxic, and we identify promising hits for further optimization as modulators of the NMDAR function.-
dc.description.sponsorshipThis work was supported by FCT (Fundaç~ao para a Ci^encia e a Tecnologia, I.P.) through iMed.ULisboa (UID/DTP/04138/2019), Principal Researcher grant CEECIND/01772/2017 (M. M. M. Santos), and PhD fellowships SFRH/BD/117931/2016 (M. Espadinha) and SFRH/BD/121664/2016 (R. Lopes). Financial support from FCT and Portugal 2020 to the Portuguese Mass Spectrometry Network (Rede Nacional de Espectrometria de Massa e RNEM; LISBOA-01-0145- FEDER-402-022125) is also acknowledged. M.I.R.-F. thanks funding from the Spanish Ministry of Science, Innovation and Universities (grant RTI2018-093955-B-C21) and the technical assistance of Ms. Cristina Tortosa (European contract for young professionals). C.d.l.R. thanks funding from Instituto de Salud Carlos III, Madrid, Spain (grant PI16/01041 and PhD fellowship FI17/00079 for L. Viejo).-
dc.languageeng-
dc.publisherElsevier-
dc.relationinfo:eu-repo/grantAgreement/AEI/Plan Estatal de Investigación Científica y Técnica y de Innovación 2017-2020/RTI2018-093955-B-C21-
dc.rightsopenAccessen_EN
dc.subject1-Aminoindan-2-ol-
dc.subjectAntagonisms-
dc.subjectCNS-
dc.subjectEnantiomerically pure lactams-
dc.subjectNMDA recept-
dc.titleIdentification of tetracyclic lactams as NMDA receptor antagonists with potential application in neurological disorders-
dc.typeartículo-
dc.identifier.doi10.1016/j.ejmech.2020.112242-
dc.relation.publisherversionhttp://dx.doi.org/10.1016/j.ejmech.2020.112242-
dc.date.updated2020-09-04T09:40:13Z-
dc.contributor.funderFundação para a Ciência e a Tecnologia (Portugal)-
dc.contributor.funderMinisterio de Ciencia, Innovación y Universidades (España)-
dc.contributor.funderEuropean Commission-
dc.contributor.funderInstituto de Salud Carlos III-
dc.relation.csic-
dc.identifier.funderhttp://dx.doi.org/10.13039/501100000780es_ES
dc.identifier.funderhttp://dx.doi.org/10.13039/501100001871es_ES
dc.identifier.funderhttp://dx.doi.org/10.13039/501100004587es_ES
dc.type.coarhttp://purl.org/coar/resource_type/c_6501es_ES
item.openairetypeartículo-
item.cerifentitytypePublications-
item.grantfulltextopen-
item.openairecristypehttp://purl.org/coar/resource_type/c_18cf-
item.fulltextWith Fulltext-
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