Cieslikiewicz-Bouet M

References (3)

Title : Discovery of a Potent Dual Inhibitor of Acetylcholinesterase and Butyrylcholinesterase with Antioxidant Activity that Alleviates Alzheimer-like Pathology in Old APP\/PS1 Mice - Viayna_2021_J.Med.Chem_64_812
Author(s) : Viayna E , Coquelle N , Cieslikiewicz-Bouet M , Cisternas P , Oliva CA , Sanchez-Lopez E , Ettcheto M , Bartolini M , De Simone A , Ricchini M , Rendina M , Pons M , Firuzi O , Perez B , Saso L , Andrisano V , Nachon F , Brazzolotto X , Garcia ML , Camins A , Silman I , Jean L , Inestrosa NC , Colletier JP , Renard PY , Munoz-Torrero D
Ref : Journal of Medicinal Chemistry , 64 :812 , 2021
Abstract : The combination of the scaffolds of the cholinesterase inhibitor huprine Y and the antioxidant capsaicin results in compounds with nanomolar potencies toward human acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) that retain or improve the antioxidant properties of capsaicin. Crystal structures of their complexes with AChE and BChE revealed the molecular basis for their high potency. Brain penetration was confirmed by biodistribution studies in C57BL6 mice, with one compound (5i) displaying better brain/plasma ratio than donepezil. Chronic treatment of 10 month-old APP/PS1 mice with 5i (2 mg/kg, i.p., 3 times per week, 4 weeks) rescued learning and memory impairments, as measured by three different behavioral tests, delayed the Alzheimer-like pathology progression, as suggested by a significantly reduced Abeta42/Abeta40 ratio in the hippocampus, improved basal synaptic efficacy, and significantly reduced hippocampal oxidative stress and neuroinflammation. Compound 5i emerges as an interesting anti-Alzheimer lead with beneficial effects on cognitive symptoms and on some underlying disease mechanisms.
ESTHER : Viayna_2021_J.Med.Chem_64_812
PubMedSearch : Viayna_2021_J.Med.Chem_64_812
PubMedID: 33356266
Gene_locus related to this paper: human-ACHE

Title : Functional characterization of multifunctional ligands targeting acetylcholinesterase and alpha 7 nicotinic acetylcholine receptor - Cieslikiewicz-Bouet_2020_Biochem.Pharmacol__114010
Author(s) : Cieslikiewicz-Bouet M , Naldi M , Bartolini M , Perez B , Servent D , Jean L , Araoz R , Renard PY
Ref : Biochemical Pharmacology , :114010 , 2020
Abstract : Alzheimer's disease (AD) is a neurodegenerative disorder associated with cholinergic dysfunction, provoking memory loss and cognitive dysfunction in elderly patients. The cholinergic hypothesis provided over the years with molecular targets for developing palliative treatments for AD, acting on the cholinergic system, namely, acetylcholinesterase and alpha7 nicotinic acetylcholine receptor (alpha7 nAChR). In our synthetic work, we used "click-chemistry" to synthesize two Multi Target Directed Ligands (MTDLs) MB105 and MB118 carrying tacrine and quinuclidine scaffolds which are known for their anticholinesterase and alpha7 nicotinic acetylcholine receptor agonist activities, respectively. Both, MB105 and MB118, inhibit human acetylcholinesterase and human butyrylcholinesterase in the nanomolar range. Electrophysiological recordings on Xenopus laevis oocytes expressing human alpha7 nAChR showed that MB105 and MB118 acted as partial agonists of the referred nicotinic receptor, albeit, with different potencies despite their similar structure. The different substitution at C-3 on the 2,3-disubtituted quinuclidine scaffold may account for the significantly lower potency of MB118 compared to MB105. Electrophysiological recordings showed that the tacrine precursor MB320 behaved as a competitive antagonist of human alpha7 nAChR, in the micromolar range, while the quinuclidine synthetic precursor MB099 acted as a partial agonist. Taken all together, MB105 behaved as a partial agonist of alpha7 nAChR at concentrations where it completely inhibited human acetylcholinesterase activity paving the way for the design of novel MTDLs for palliative treatment of AD.
ESTHER : Cieslikiewicz-Bouet_2020_Biochem.Pharmacol__114010
PubMedSearch : Cieslikiewicz-Bouet_2020_Biochem.Pharmacol__114010
PubMedID: 32360492

Title : Increasing Polarity in Tacrine and Huprine Derivatives: Potent Anticholinesterase Agents for the Treatment of Myasthenia Gravis - Galdeano_2018_Molecules_23_
Author(s) : Galdeano C , Coquelle N , Cieslikiewicz-Bouet M , Bartolini M , Perez B , Clos MV , Silman I , Jean L , Colletier JP , Renard PY , Munoz-Torrero D
Ref : Molecules , 23 : , 2018
Abstract : Symptomatic treatment of myasthenia gravis is based on the use of peripherally-acting acetylcholinesterase (AChE) inhibitors that, in some cases, must be discontinued due to the occurrence of a number of side-effects. Thus, new AChE inhibitors are being developed and investigated for their potential use against this disease. Here, we have explored two alternative approaches to get access to peripherally-acting AChE inhibitors as new agents against myasthenia gravis, by structural modification of the brain permeable anti-Alzheimer AChE inhibitors tacrine, 6-chlorotacrine, and huprine Y. Both quaternization upon methylation of the quinoline nitrogen atom, and tethering of a triazole ring, with, in some cases, the additional incorporation of a polyphenol-like moiety, result in more polar compounds with higher inhibitory activity against human AChE (up to 190-fold) and butyrylcholinesterase (up to 40-fold) than pyridostigmine, the standard drug for symptomatic treatment of myasthenia gravis. The novel compounds are furthermore devoid of brain permeability, thereby emerging as interesting leads against myasthenia gravis.
ESTHER : Galdeano_2018_Molecules_23_
PubMedSearch : Galdeano_2018_Molecules_23_
PubMedID: 29534488
Gene_locus related to this paper: torca-ACHE