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http://hdl.handle.net/10261/219127
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dc.contributor.author | Espadinha, Margarida | - |
dc.contributor.author | Viejo, L. | - |
dc.contributor.author | Lopes, R. M. R. M. | - |
dc.contributor.author | Herrera-Arozamena, Clara | - |
dc.contributor.author | Molins, E. | - |
dc.contributor.author | dos Santos, D. J. V. A. | - |
dc.contributor.author | Gonçalves, Lídia M. | - |
dc.contributor.author | Rodríguez-Franco, María Isabel | - |
dc.contributor.author | Ríos, C. d. l. | - |
dc.contributor.author | Santos, Maria M. M. | - |
dc.date.accessioned | 2020-09-04T09:40:13Z | - |
dc.date.available | 2020-09-04T09:40:13Z | - |
dc.date.issued | 2020 | - |
dc.identifier | doi: 10.1016/j.ejmech.2020.112242 | - |
dc.identifier | issn: 1768-3254 | - |
dc.identifier.citation | European Journal of Medicinal Chemistry 194 (2020) | - |
dc.identifier.uri | http://hdl.handle.net/10261/219127 | - |
dc.description.abstract | N-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.sponsorship | This 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.language | eng | - |
dc.publisher | Elsevier | - |
dc.relation | info:eu-repo/grantAgreement/AEI/Plan Estatal de Investigación Científica y Técnica y de Innovación 2017-2020/RTI2018-093955-B-C21 | - |
dc.rights | openAccess | en_EN |
dc.subject | 1-Aminoindan-2-ol | - |
dc.subject | Antagonisms | - |
dc.subject | CNS | - |
dc.subject | Enantiomerically pure lactams | - |
dc.subject | NMDA recept | - |
dc.title | Identification of tetracyclic lactams as NMDA receptor antagonists with potential application in neurological disorders | - |
dc.type | artículo | - |
dc.identifier.doi | 10.1016/j.ejmech.2020.112242 | - |
dc.relation.publisherversion | http://dx.doi.org/10.1016/j.ejmech.2020.112242 | - |
dc.date.updated | 2020-09-04T09:40:13Z | - |
dc.contributor.funder | Fundação para a Ciência e a Tecnologia (Portugal) | - |
dc.contributor.funder | Ministerio de Ciencia, Innovación y Universidades (España) | - |
dc.contributor.funder | European Commission | - |
dc.contributor.funder | Instituto de Salud Carlos III | - |
dc.relation.csic | Sí | - |
dc.identifier.funder | http://dx.doi.org/10.13039/501100000780 | es_ES |
dc.identifier.funder | http://dx.doi.org/10.13039/501100001871 | es_ES |
dc.identifier.funder | http://dx.doi.org/10.13039/501100004587 | es_ES |
dc.type.coar | http://purl.org/coar/resource_type/c_6501 | es_ES |
item.openairetype | artículo | - |
item.cerifentitytype | Publications | - |
item.grantfulltext | open | - |
item.openairecristype | http://purl.org/coar/resource_type/c_18cf | - |
item.fulltext | With Fulltext | - |
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20 EJMC 112242 Postprint (Identification of tetracyclic lactams).pdf | 920,07 kB | Adobe PDF | Visualizar/Abrir |
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