273748-51-9Relevant articles and documents
Functional characterization of multifunctional ligands targeting acetylcholinesterase and alpha 7 nicotinic acetylcholine receptor
Aráoz, Rómulo,Bartolini, Manuela,Cieslikiewicz-Bouet, Monika,Jean, Ludovic,Naldi, Marina,Pérez, Belén,Renard, Pierre-Yves,Servent, Denis
, (2020)
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 acetylcholinesterase activity paving the way for the design of novel MTDLs for palliative treatment of AD.
1,4-DISUBSTITUTED 1,2,3-TRIAZOLES, METHODS FOR PREPARING SAME, AND DIAGNOSTIC AND THERAPEUTIC USES THEREOF
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Paragraph 0574; 0576, (2014/02/16)
A compound having the following general formula (I): wherein: X is a nitrogen atom and Y is a carbon atom; orX is a carbon atom and Y is a nitrogen atom;the Ar group is an aryl or heteroaryl group; andthe RN and RN′ groups, together with the carbon atoms
Surface plasmon resonance biosensor based fragment screening using acetylcholine binding protein identifies ligand efficiency hot spots (le hot spots) by deconstruction of nicotinic acetylcholine receptor α7 ligands
De Kloe, Gerdien E.,Retra, Kim,Geitmann, Matthis,K?llblad, Per,Nahar, Tariq,Van Elk, René,Smit, August B.,Van Muijlwijk-Koezen, Jacqueline E.,Leurs, Rob,Irth, Hubertus,Danielson, U. Helena,De Esch, Iwan J. P.
experimental part, p. 7192 - 7201 (2010/12/18)
The soluble acetylcholine binding protein (AChBP) is a homologue of the ligand-binding domain of the nicotinic acetylcholine receptors (nAChR). To guide future fragment-screening using surface plasmon resonance (SPR) biosensor technology as a label-free, direct binding, biophysical screening assay, a focused fragment library was generated based on deconstruction of a set of α7 nAChR selective quinuclidine containing ligands with nanomolar affinities. The interaction characteristics of the fragments and the parent compounds with AChBP were evaluated using an SPR biosensor assay. The data obtained from this direct binding assay correlated well with data from the reference radioligand displacement assay. Ligand efficiencies for different (structural) groups of fragments in the library were correlated to binding with distinct regions of the binding pocket, thereby identifying ligand efficiency hot spots (LE hot spots). These hot spots can be used to identity the most promising hit fragments in a large scale fragment library screen.
