Functional characterization of multifunctional ligands targeting acetylcholinesterase and alpha 7 nicotinic acetylcholine receptor

[Display omitted] •A rational design of a novel Multi Target Directed Ligand family targeting human acetylcholinesterase and α7 nicotinic acetylcholine receptor led to the synthesis of MB105 and MB118 by using copper(I)-catalyzed azide alkyne cycloaddition click-chemistry.•The Multi Target Directed...

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Bibliographic Details
Published in:	Biochemical pharmacology 2020-07, Vol.177, p.114010, Article 114010
Main Authors:	Cieslikiewicz-Bouet, Monika, Naldi, Marina, Bartolini, Manuela, Pérez, Belén, Servent, Denis, Jean, Ludovic, Aráoz, Rómulo, Renard, Pierre-Yves
Format:	Article
Language:	eng
Subjects:	Acetylcholinesterase Alkynes - chemistry Alpha 7 nicotinic acetylcholine receptor alpha7 Nicotinic Acetylcholine Receptor - agonists alpha7 Nicotinic Acetylcholine Receptor - antagonists & inhibitors alpha7 Nicotinic Acetylcholine Receptor - genetics alpha7 Nicotinic Acetylcholine Receptor - metabolism Alzheimer Disease - drug therapy Alzheimer’s disease Animals Blood-Brain Barrier - drug effects Butyrylcholinesterase Butyrylcholinesterase - metabolism Catalysis Chemical Sciences Cholinesterase Inhibitors - chemical synthesis Cholinesterase Inhibitors - chemistry Cholinesterase Inhibitors - pharmacology Click Chemistry Copper Cycloaddition Reaction Dose-Response Relationship, Drug Drug Design Drug Evaluation, Preclinical Female Humans Ligands Medicinal Chemistry Molecular Docking Simulation Molecular Structure Multi-target directed ligand Structure-Activity Relationship Tacrine - chemistry Tacrine - pharmacology Xenopus laevis
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Summary:	[Display omitted] •A rational design of a novel Multi Target Directed Ligand family targeting human acetylcholinesterase and α7 nicotinic acetylcholine receptor led to the synthesis of MB105 and MB118 by using copper(I)-catalyzed azide alkyne cycloaddition click-chemistry.•The Multi Target Directed Ligands MB105 and MB118 inhibit human acetylcholinesterase and butyrylcholinesterase in the nanomolar range.•Tacrine and the synthetic precursor MB320 competitively antagonize human α7 nicotinic acetylcholine receptor in the micromolar rangeMB105 is a better partial antagonist of human α7 nicotinic acetylcholine receptor than its synthetic precursor MB099.•MB105 induced a long-lasting desensitization of the α7 nicotinic acetylcholine receptor.•At concentrations at which MB105 completely inhibits acetylcholinesterase activity, it partially antagonizes α7 nicotinic acetylcholine receptor and shows a good in vitro Blood-Brain Barrier (BBB) permeation. 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 α7 nicotinic acetylcholine receptor (α7 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 α7 nAChR 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 α7 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-disubstituted quinuclidine scaffold may account for the significantly lower potency of MB118 compared to MB105. Electrophysiological recordings also showed that the tacrine precursor MB320 behaved as a competitive antagonist of human α7 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 α7 nAChR at concentrations where it completely inhibited human acetylcholinesteras
ISSN:	0006-2952 1873-2968