We describe the development of quinolylnitrones(QNs)as multifunctional ligands inhibiting cholinesterases(ChEs:acetylcholinesterase and butyrylcholinesterase—h BChE)and monoamine oxidases(hMAO-A/B)for the therapy of ...
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We describe the development of quinolylnitrones(QNs)as multifunctional ligands inhibiting cholinesterases(ChEs:acetylcholinesterase and butyrylcholinesterase—h BChE)and monoamine oxidases(hMAO-A/B)for the therapy of neurodegenerative diseases.We identified QN 19,a simple,low molecular weight nitrone,that is readily synthesized from commercially available 8-hydroxyquinoline-2-carbaldehyde.Quinolylnitrone 19 has no typical pharmacophoric element to suggest ChE or MAO inhibition,yet unexpectedly showed potent inhibition of h BChE(IC50=1.06±0.31 nmol/L)and h MAO-B(IC_(50)=4.46±0.18μmol/L).The crystal structures of 19 with hBChE and hMAO-B provided the structural basis for potent binding,which was further studied by enzyme kinetics.Compound 19 acted as a free radical scavenger and biometal chelator,crossed the blood—brain barrier,was not cytotoxic,and showed neuroprotective properties in a 6-hydroxydopamine cell model of Parkinson's disease.In addition,in vivo studies showed the anti-amnesic effect of 19 in the scopolamine-induced mouse model of AD without adverse effects on motoric function and coordination.Importantly,chronic treatment of double transgenic APPswe-PS1δE9 mice with 19 reduced amyloid plaque load in the hippocampus and cortex of female mice,underscoring the disease-modifying effect of QN 19.
Metyrapone (2-methyl-1,2-di-3-pyridyl-1-propanone) is a drug largely used as inhibitor of glucocorticoid synthesis. Although its binding to various proteins has been well indentified, its accurate molecular mechanism ...
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Metyrapone (2-methyl-1,2-di-3-pyridyl-1-propanone) is a drug largely used as inhibitor of glucocorticoid synthesis. Although its binding to various proteins has been well indentified, its accurate molecular mechanism of action remains unknown. Therefore, the interactions of metyrapone (MET) with various membrane components such as phospholipids, cholesterol, their corresponding polar heads and a model serine containing peptide have been investigated by NMR and ESR methods. It was found that neither cholesterol nor most of the phospholipids tested, nor dimyristin exhibit any interaction with MET, except phosphatidylserine (DMPS). Furthermore, only serine bearing polar head (O-phosphoserine) showed an association with MET (stoechiometry 1:1, Kd = 3200M-1). As similar observations were also performed on serine alone and in the presence of the serine containing model peptide, (NASDSDGQDL), a possible implication of these interactions in the binding recognition of MET on serine-containing active site was finally tested and discussed.
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