{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,11]],"date-time":"2026-10-11T02:48:03Z","timestamp":1791686883807,"version":"4.3.4"},"reference-count":27,"publisher":"MDPI AG","issue":"15","license":[{"start":{"date-parts":[[2019,7,31]],"date-time":"2019-07-31T00:00:00Z","timestamp":1564531200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100014808","name":"Fondation Vaincre Alzheimer","doi-asserted-by":"publisher","award":["FR-15072"],"award-info":[{"award-number":["FR-15072"]}],"id":[{"id":"10.13039\/100014808","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100007494","name":"Fondation Plan Alzheimer","doi-asserted-by":"publisher","award":["TRIAD 016"],"award-info":[{"award-number":["TRIAD 016"]}],"id":[{"id":"10.13039\/501100007494","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Conseil R\u00e9gional de Normandie","award":["RIN"],"award-info":[{"award-number":["RIN"]}]},{"name":"European Cost Action Mu Ta Lig","award":["CA15135"],"award-info":[{"award-number":["CA15135"]}]},{"DOI":"10.13039\/501100002924","name":"FEDER","doi-asserted-by":"publisher","award":["CERMN"],"award-info":[{"award-number":["CERMN"]}],"id":[{"id":"10.13039\/501100002924","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Molecules"],"abstract":"<jats:p>Alzheimer\u2019s disease (AD) is a multifactorial neurodegenerative disease which is still poorly understood. The drugs currently used against AD, mainly acetylcholinesterase inhibitors (AChEI), are considered clinically insufficient and are responsible for deleterious side effects. AChE is, however, currently receiving renewed interest through the discovery of a chaperone role played in the pathogenesis of AD. But AChE could also serve as an activating protein for pleiotropic prodrugs. Indeed, inhibiting central AChE with brain-penetrating designed carbamates which are able to covalently bind to the enzyme and to concomitantly liberate active metabolites in the brain could constitute a clinically more efficient approach which, additionally, is less likely to cause peripheral side effects. We aim in this article to pave the road of this new avenue with an in vitro and in vivo study of pleiotropic prodrugs targeting both the 5-HT4 receptor and AChE, in order to display a neuroprotective activity associated with a sustained restoration of the cholinergic neurotransmission and without the usual peripheral side effects associated with classic AChEI. This plural activity could bring to AD patients effective, relatively safe, symptomatic and disease-modifying therapeutic benefits.<\/jats:p>","DOI":"10.3390\/molecules24152786","type":"journal-article","created":{"date-parts":[[2019,7,31]],"date-time":"2019-07-31T11:37:07Z","timestamp":1564573027000},"page":"2786","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":33,"title":["Inhibiting Acetylcholinesterase to Activate Pleiotropic Prodrugs with Therapeutic Interest in Alzheimer\u2019s Disease"],"prefix":"10.3390","volume":"24","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5630-6920","authenticated-orcid":false,"given":"Fran\u00e7ois-Xavier","family":"Toublet","sequence":"first","affiliation":[{"name":"Normandie Univ, UNICAEN, CERMN, 14000 Caen, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"C\u00e9dric","family":"Lecoutey","sequence":"additional","affiliation":[{"name":"Normandie Univ, UNICAEN, CERMN, 14000 Caen, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Julien","family":"Lalut","sequence":"additional","affiliation":[{"name":"Normandie Univ, UNICAEN, CERMN, 14000 Caen, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"B\u00e9r\u00e9nice","family":"Hatat","sequence":"additional","affiliation":[{"name":"Normandie Univ, UNICAEN, CERMN, 14000 Caen, France"},{"name":"Univ. Montpellier, CNRS, INSERM, IGF, 34090 Montpellier, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Audrey","family":"Davis","sequence":"additional","affiliation":[{"name":"Normandie Univ, UNICAEN, CERMN, 14000 Caen, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3984-5812","authenticated-orcid":false,"given":"Marc","family":"Since","sequence":"additional","affiliation":[{"name":"Normandie Univ, UNICAEN, CERMN, 14000 Caen, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sophie","family":"Corvaisier","sequence":"additional","affiliation":[{"name":"Normandie Univ, UNICAEN, CERMN, 14000 Caen, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4446-4451","authenticated-orcid":false,"given":"Thomas","family":"Freret","sequence":"additional","affiliation":[{"name":"Normandie Univ, UNICAEN, INSERM, Comete, GIP CYCERON, 14000 Caen, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jana","family":"Sopkova de Oliveira Santos","sequence":"additional","affiliation":[{"name":"Normandie Univ, UNICAEN, CERMN, 14000 Caen, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0576-5518","authenticated-orcid":false,"given":"Sylvie","family":"Claeysen","sequence":"additional","affiliation":[{"name":"Univ. Montpellier, CNRS, INSERM, IGF, 34090 Montpellier, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michel","family":"Boulouard","sequence":"additional","affiliation":[{"name":"Normandie Univ, UNICAEN, INSERM, Comete, GIP CYCERON, 14000 Caen, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4845-615X","authenticated-orcid":false,"given":"Patrick","family":"Dallemagne","sequence":"additional","affiliation":[{"name":"Normandie Univ, UNICAEN, CERMN, 14000 Caen, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7996-2082","authenticated-orcid":false,"given":"Christophe","family":"Rochais","sequence":"additional","affiliation":[{"name":"Normandie Univ, UNICAEN, CERMN, 14000 Caen, France"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2019,7,31]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"131","DOI":"10.1016\/j.neuropharm.2019.05.025","article-title":"New evidence for dual binding site inhibitors of acetylcholinesterase as improved drugs for treatment of Alzheimer\u2019s disease","volume":"155","author":"Zueva","year":"2019","journal-title":"Neuropharmacology"},{"key":"ref_2","unstructured":"(2019, July 08). ClinicalTrials.gov, Available online: https:\/\/clinicaltrials.gov\/."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"200","DOI":"10.1016\/j.ejmech.2019.02.076","article-title":"Advancement of multi-target drug discoveries and promising applications in the field of Alzheimer\u2019s disease","volume":"169","author":"Wang","year":"2019","journal-title":"Eur. J. Med. Chem."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"E3825","DOI":"10.1073\/pnas.1410315111","article-title":"Design of donecopride, a dual serotonin subtype 4 receptor agonist\/acetylcholinesterase inhibitor with potential interest for Alzheimer\u2019s disease treatment","volume":"111","author":"Lecoutey","year":"2014","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"3172","DOI":"10.1021\/acs.jmedchem.5b00115","article-title":"Novel multitarget-directed ligands (MTDLs) with acetylcholinesterase (AChE) inhibitory and serotonergic subtype 4 receptor (5-HT4R) agonist activities as potential agents against Alzheimer\u2019s disease: The design of donecopride","volume":"58","author":"Rochais","year":"2015","journal-title":"J. Med. Chem."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"2177","DOI":"10.1096\/fj.05-4910fje","article-title":"A multifunctional, neuroprotective drug, ladostigil (TV3326), regulates holo-APP translation and processing","volume":"20","author":"Amit","year":"2006","journal-title":"Faseb J."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"836","DOI":"10.1016\/j.neuropharm.2006.10.005","article-title":"Ladostigil prevents gliosis, oxidative\u2013nitrative stress and memory deficits induced by intracerebroventricular injection of streptozotocin in rats","volume":"52","author":"Shoham","year":"2007","journal-title":"Neuropharmacology"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"852","DOI":"10.1021\/acschemneuro.8b00391","article-title":"Reconsideration of anticholinesterase therapeutic strategies against Alzheimer\u2019s disease","volume":"10","author":"Wang","year":"2019","journal-title":"Acs Chem. Neurosci."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"781","DOI":"10.1016\/j.ejmech.2018.07.056","article-title":"Multi-target-directed ligands for Alzheimer\u2019s disease: Discovery of chromone-based monoamine oxidase\/cholinesterase inhibitors","volume":"158","author":"Reis","year":"2018","journal-title":"Eur. J. Med. Chem."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"1304","DOI":"10.1016\/j.bmc.2017.03.067","article-title":"Synthesis of enantiomerically enriched drug precursors and an insect pheromone via reduction of ketones using commercially available carbonyl reductase screening kit \u201cChiralscreen\u00ae OH.\u201d","volume":"26","author":"Nagai","year":"2018","journal-title":"Bioorg. Med. Chem."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"951","DOI":"10.1016\/S0040-4039(00)01953-5","article-title":"An expedient and highly selective iodination of alcohols using a KI\/BF3.Et2O system","volume":"42","author":"Bandgar","year":"2001","journal-title":"Tetrahedron Lett."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"105","DOI":"10.1016\/j.bioorg.2016.06.002","article-title":"Insights into (S)-rivastigmine inhibition of butyrylcholinesterase (BuChE): Molecular docking and saturation transfer difference NMR (STD-NMR)","volume":"67","author":"Bacalhau","year":"2016","journal-title":"Bioorg. Chem."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"10282","DOI":"10.1021\/jm300871x","article-title":"Structures of human acetylcholinesterase in complex with pharmacologically important ligands","volume":"55","author":"Cheung","year":"2012","journal-title":"J. Med. Chem."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"88","DOI":"10.1016\/0006-2952(61)90145-9","article-title":"A new and rapid colorimetric determination of acetylcholinesterase activity","volume":"7","author":"Ellman","year":"1961","journal-title":"Biochem. Pharm."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"618","DOI":"10.1111\/j.1476-5381.1993.tb13617.x","article-title":"Development of a radioligand binding assay for 5-HT4 receptors in guinea-pig and rat brain","volume":"109","author":"Grossman","year":"1993","journal-title":"Br. J. Pharm."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"3684","DOI":"10.1021\/jm010491d","article-title":"Anticholinesterase activity of compounds related to geneserine tautomers. N -oxides and 1,2-oxazines \u2016","volume":"45","author":"Yu","year":"2002","journal-title":"J. Med. Chem."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"224","DOI":"10.1159\/000280418","article-title":"Investigations into the binding affinities of different human 5-HT4 receptor splice variants","volume":"85","author":"Irving","year":"2010","journal-title":"Pharmacology"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"65","DOI":"10.4062\/biomolther.2010.18.1.065","article-title":"The inhibitory effect of rivastigmine and galantamine on choline transport in brain capillary endothelial cells","volume":"18","author":"Lee","year":"2010","journal-title":"Biomol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"18387","DOI":"10.1021\/acsomega.8b02121","article-title":"Dihydroquinoline carbamate DQS1-02 as a prodrug of a potent acetylcholinesterase inhibitor for Alzheimer\u2019s disease therapy: Multigram-scale synthesis, mechanism investigations, in vitro safety pharmacology, and preliminary in vivo toxicology profile","volume":"3","author":"Alix","year":"2018","journal-title":"Acs Omega"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"53","DOI":"10.1007\/s00213-008-1394-2","article-title":"Methylthioninium chloride reverses cognitive deficits induced by scopolamine: Comparison with rivastigmine","volume":"202","author":"Deiana","year":"2009","journal-title":"Psychopharmacology"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.ejphar.2009.03.054","article-title":"BZYX. A novel acetylcholinesterase inhibitor, significantly improved chemicals-induced learning and memory impairments on rodents and protected PC12 cells from apoptosis induced by hydrogen peroxide","volume":"613","author":"Zhang","year":"2009","journal-title":"Eur. J. Pharm."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"584","DOI":"10.1016\/j.bbr.2010.01.004","article-title":"WIN55,212-2 induced deficits in spatial learning are mediated by cholinergic hypofunction","volume":"208","author":"Robinson","year":"2010","journal-title":"Behav. Brain Res."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"43","DOI":"10.1016\/S0022-2836(95)80037-9","article-title":"Molecular recognition of receptor sites using a genetic algorithm with a description of desolvation","volume":"245","author":"Jones","year":"1995","journal-title":"J. Mol. Biol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"727","DOI":"10.1006\/jmbi.1996.0897","article-title":"Development and validation of a genetic algorithm for flexible docking","volume":"267","author":"Jones","year":"1997","journal-title":"J. Mol. Biol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"627","DOI":"10.1039\/c2md20063e","article-title":"Synthesis of dual AChE\/5-HT4 receptor multi-target directed ligands","volume":"3","author":"Lecoutey","year":"2012","journal-title":"Medchemcomm"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"304","DOI":"10.1016\/j.bbr.2012.02.012","article-title":"Synergistic effect of acetylcholinesterase inhibition (donepezil) and 5-HT4 receptor activation (RS67333) on object recognition in mice","volume":"230","author":"Freret","year":"2012","journal-title":"Behav. Brain Res."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"250","DOI":"10.1007\/BF02246579","article-title":"Effects of purine analogues on spontaneous alternation in mice","volume":"123","author":"Hooper","year":"1996","journal-title":"Psychopharmacology"}],"container-title":["Molecules"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1420-3049\/24\/15\/2786\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T13:11:39Z","timestamp":1760188299000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1420-3049\/24\/15\/2786"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2019,7,31]]},"references-count":27,"journal-issue":{"issue":"15","published-online":{"date-parts":[[2019,8]]}},"alternative-id":["molecules24152786"],"URL":"https:\/\/doi.org\/10.3390\/molecules24152786","relation":{},"ISSN":["1420-3049"],"issn-type":[{"value":"1420-3049","type":"electronic"}],"subject":[],"published":{"date-parts":[[2019,7,31]]}}}