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http://hdl.handle.net/10261/152985
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dc.contributor.author | Unzeta, Mercedes | - |
dc.contributor.author | Esteban, Gerard | - |
dc.contributor.author | Bolea, Irene | - |
dc.contributor.author | Fogel, W. Agnieszka | - |
dc.contributor.author | Ramsay, Rona R. | - |
dc.contributor.author | Youdim, Moussa B. H. | - |
dc.contributor.author | Tipton, Keith Francis | - |
dc.contributor.author | Marco-Contelles, José | - |
dc.date.accessioned | 2017-07-14T11:45:10Z | - |
dc.date.available | 2017-07-14T11:45:10Z | - |
dc.date.issued | 2016-05-25 | - |
dc.identifier.citation | Frontiers in Neuroscience 10: 205 (2016) | - |
dc.identifier.issn | 1662-4548 | - |
dc.identifier.uri | http://hdl.handle.net/10261/152985 | - |
dc.description.abstract | HIGHLIGHTSASS234 is a MTDL compound containing a moiety from Donepezil and the propargyl group from the PF 9601N, a potent and selective MAO B inhibitor. This compound is the most advanced anti-Alzheimer agent for preclinical studies identified in our laboratory.Derived from ASS234 both multipotent donepezil-indolyl (MTDL-1) and donepezil-pyridyl hybrids (MTDL-2) were designed and evaluated as inhibitors of AChE/BuChE and both MAO isoforms. MTDL-2 showed more high affinity toward the four enzymes than MTDL-1.MTDL-3 and MTDL-4, were designed containing the N-benzylpiperidinium moiety from Donepezil, a metal- chelating 8-hydroxyquinoline group and linked to a N-propargyl core and they were pharmacologically evaluated.The presence of the cyano group in MTDL-3, enhanced binding to AChE, BuChE and MAO A. It showed antioxidant behavior and it was able to strongly complex Cu(II), Zn(II) and Fe(III).MTDL-4 showed higher affinity toward AChE, BuChE.MTDL-3 exhibited good brain penetration capacity (ADMET) and less toxicity than Donepezil. Memory deficits in scopolamine-lesioned animals were restored by MTDL-3.MTDL-3 particularly emerged as a ligand showing remarkable potential benefits for its use in AD therapy.Alzheimer's disease (AD), the most common form of adult onset dementia, is an age-related neurodegenerative disorder characterized by progressive memory loss, decline in language skills, and other cognitive impairments. Although its etiology is not completely known, several factors including deficits of acetylcholine, β-amyloid deposits, τ-protein phosphorylation, oxidative stress, and neuroinflammation are considered to play significant roles in the pathophysiology of this disease. For a long time, AD patients have been treated with acetylcholinesterase inhibitors such as donepezil (Aricept®) but with limited therapeutic success. This might be due to the complex multifactorial nature of AD, a fact that has prompted the design of new Multi-Target-Directed Ligands (MTDL) based on the “one molecule, multiple targets” paradigm. Thus, in this context, different series of novel multifunctional molecules with antioxidant, anti-amyloid, anti-inflammatory, and metal-chelating properties able to interact with multiple enzymes of therapeutic interest in AD pathology including acetylcholinesterase, butyrylcholinesterase, and monoamine oxidases A and B have been designed and assessed biologically. This review describes the multiple targets, the design rationale and an in-house MTDL library, bearing the N-benzylpiperidine motif present in donepezil, linked to different heterocyclic ring systems (indole, pyridine, or 8-hydroxyquinoline) with special emphasis on compound ASS234, an N-propargylindole derivative. The description of the in vitro biological properties of the compounds and discussion of the corresponding structure-activity-relationships allows us to highlight new issues for the identification of more efficient MTDL for use in AD therapy. | - |
dc.description.sponsorship | MU, GE, JM thank to MIneco (Spain) for support Grant SAF 2012-33304, SAF 2015-65586R. All authors thank EU COST Action CM1103 for its support. | - |
dc.publisher | Frontiers Media | - |
dc.relation | info:eu-repo/grantAgreement/MINECO/Plan Estatal de Investigación Científica y Técnica y de Innovación 2013-2016MINECO/ICTI2013‐2016/SAF2015-65586-R | - |
dc.relation.isversionof | Publisher's version | - |
dc.rights | openAccess | - |
dc.title | Multi-Target Directed Donepezil-Like Ligands for Alzheimer's Disease | - |
dc.type | artículo | - |
dc.identifier.doi | 10.3389/fnins.2016.00205 | - |
dc.description.peerreviewed | Peer reviewed | - |
dc.relation.publisherversion | http://dx.doi.org/10.3389/fnins.2016.00205 | - |
dc.date.updated | 2017-07-14T11:45:10Z | - |
dc.description.version | Peer Reviewed | - |
dc.language.rfc3066 | en | - |
dc.rights.holder | Copyright © 2016 Unzeta, Esteban, Bolea, Fogel, Ramsay, Youdim, Tipton and Marco-Contelles. | - |
dc.rights.license | http://creativecommons.org/licenses/by/4.0/ | - |
dc.contributor.funder | Ministerio de Economía y Competitividad (España) | - |
dc.relation.csic | Sí | - |
dc.identifier.funder | http://dx.doi.org/10.13039/501100003329 | es_ES |
dc.identifier.pmid | 27252617 | - |
dc.type.coar | http://purl.org/coar/resource_type/c_6501 | es_ES |
item.cerifentitytype | Publications | - |
item.openairecristype | http://purl.org/coar/resource_type/c_18cf | - |
item.grantfulltext | open | - |
item.openairetype | artículo | - |
item.fulltext | With Fulltext | - |
Aparece en las colecciones: | (IQOG) Artículos |
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Fichero | Descripción | Tamaño | Formato | |
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Multi-Target Directed Donepezil-Like.pdf | 6,08 MB | Adobe PDF | Visualizar/Abrir |
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