Huprine-tacrine heterodimers as anti-amyloidogenic compounds of potential interest against Alzheimer's and prion diseases.

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Galdeano C, Viayna E, Sola I, Formosa X, Camps P, Badia A, Clos MV, Relat J, Ratia M, Bartolini M, Mancini F, Andrisano V, Salmona M, Minguillon C, Gonzalez-Munoz GC, Rodriguez-Franco MI, Bidon-Chanal A, Luque FJ, Munoz-Torrero D

Huprine-tacrine heterodimers as anti-amyloidogenic compounds of potential interest against Alzheimer's and prion diseases.

J Med Chem. 2012 Jan 26;55(2):661-9. doi: 10.1021/jm200840c. Epub 2012 Jan 10.

PubMed ID

22185619 [ View in PubMed

]

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 beta-amyloid peptide (Abeta) 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 Abeta aggregation, and beta-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.

DrugBank Data that Cites this Article

Binding Properties

Drug	Target	Property	Measurement	pH	Temperature (°C)
Tacrine	Acetylcholinesterase	IC 50 (nM)	317	N/A	N/A	Details