Abstract
A family of huprine-tacrine heterodimers has been developed to simultaneously block the active and peripheral sites of acetylcholinesterase (AChE). Their dual site binding for AChE, supported by kinetic and molecular modeling studies, results in a highly potent inhibition of the catalytic activity of human AChE and, more importantly, in the in vitro neutralization of the pathological chaperoning effect of AChE toward the aggregation of both the β-amyloid peptide (Aβ) and a prion peptide with a key role in the aggregation of the prion protein. Huprine-tacrine heterodimers take on added value in that they display a potent in vitro inhibitory activity toward human butyrylcholinesterase, self-induced Aβ aggregation, and β-secretase. Finally, they are able to cross the blood-brain barrier, as predicted in an artificial membrane model assay and demonstrated in ex vivo experiments with OF1 mice, reaching their multiple biological targets in the central nervous system. Overall, these compounds are promising lead compounds for the treatment of Alzheimer's and prion diseases.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Acetylcholinesterase / chemistry
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Acetylcholinesterase / metabolism
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Alzheimer Disease / drug therapy*
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Aminoquinolines / chemical synthesis*
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Aminoquinolines / pharmacokinetics
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Aminoquinolines / pharmacology
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Amyloid beta-Peptides / antagonists & inhibitors*
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Amyloid beta-Peptides / chemistry
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Animals
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Brain / metabolism
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Butyrylcholinesterase / chemistry
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Cholinesterase Inhibitors / chemical synthesis*
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Cholinesterase Inhibitors / pharmacokinetics
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Cholinesterase Inhibitors / pharmacology
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Heterocyclic Compounds, 4 or More Rings / chemical synthesis*
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Heterocyclic Compounds, 4 or More Rings / pharmacokinetics
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Heterocyclic Compounds, 4 or More Rings / pharmacology
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Humans
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Membranes, Artificial
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Mice
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Models, Molecular
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Peptide Fragments / antagonists & inhibitors
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Peptide Fragments / chemistry
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Permeability
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Prion Diseases / drug therapy*
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Prions / antagonists & inhibitors*
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Prions / chemistry
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Recombinant Proteins / chemistry
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Stereoisomerism
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Structure-Activity Relationship
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Tacrine / analogs & derivatives*
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Tacrine / chemical synthesis*
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Tacrine / pharmacokinetics
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Tacrine / pharmacology
Substances
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Aminoquinolines
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Amyloid beta-Peptides
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Cholinesterase Inhibitors
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Heterocyclic Compounds, 4 or More Rings
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Membranes, Artificial
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Peptide Fragments
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Prions
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Recombinant Proteins
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huprine Y
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Tacrine
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Acetylcholinesterase
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Butyrylcholinesterase