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Multi-target directed donepezil-like ligands for Alzheimer's disease
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dc.contributor.author | Unzeta, Mercedes | |
dc.contributor.author | Esteban, Gerard | |
dc.contributor.author | Bolea, Irene | |
dc.contributor.author | Fogel, Wieslawa Agnieszka | |
dc.contributor.author | Ramsay, Rona R. | |
dc.contributor.author | Youdim, Moussa B. H. | |
dc.contributor.author | Tipton, Keith F. | |
dc.contributor.author | Marco-Contelles, José | |
dc.date.accessioned | 2016-06-17T12:30:07Z | |
dc.date.available | 2016-06-17T12:30:07Z | |
dc.date.issued | 2016-05 | |
dc.identifier | 243473179 | |
dc.identifier | a474edf9-942d-4e1d-9eae-cd52160fc430 | |
dc.identifier | 84973535638 | |
dc.identifier | 000376631200001 | |
dc.identifier.citation | Unzeta , M , Esteban , G , Bolea , I , Fogel , W A , Ramsay , R R , Youdim , M B H , Tipton , K F & Marco-Contelles , J 2016 , ' Multi-target directed donepezil-like ligands for Alzheimer's disease ' , Frontiers in Neuroscience , vol. 10 , 205 . https://doi.org/10.3389/fnins.2016.00205 | en |
dc.identifier.issn | 1662-453X | |
dc.identifier.other | Bibtex: urn:2ee4aa96cc686f237a5f88353c9f6825 | |
dc.identifier.uri | https://hdl.handle.net/10023/9010 | |
dc.description | 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. | en |
dc.description.abstract | Highlights -ASS234 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.format.extent | 24 | |
dc.format.extent | 5689551 | |
dc.language.iso | eng | |
dc.relation.ispartof | Frontiers in Neuroscience | en |
dc.subject | QH301 Biology | en |
dc.subject | RC0321 Neuroscience. Biological psychiatry. Neuropsychiatry | en |
dc.subject.lcc | QH301 | en |
dc.subject.lcc | RC0321 | en |
dc.title | Multi-target directed donepezil-like ligands for Alzheimer's disease | en |
dc.type | Journal item | en |
dc.contributor.institution | University of St Andrews. School of Biology | en |
dc.contributor.institution | University of St Andrews. Biomedical Sciences Research Complex | en |
dc.identifier.doi | 10.3389/fnins.2016.00205 | |
dc.description.status | Peer reviewed | en |
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