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

Carles Galdeano, Elisabet Viayna, Irene Sola, Xavier Formosa, Pelayo Camps, Albert Badia, M. Victòria Clos, Júlia Relat, Míriam Ratia, Manuela Bartolini, Francesca Mancini, Vincenza Andrisano, Mario Salmona, Cristina Minguillón, Gema C. González-Muñoz, M. Isabel Rodríguez-Franco, Axel Bidon-Chanal, F. Javier Luque, Diego Muñoz-Torrero

Research output: Contribution to journalArticle

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.

Original languageEnglish
Pages (from-to)661-669
Number of pages9
JournalJournal of Medicinal Chemistry
Volume55
Issue number2
DOIs
Publication statusPublished - Jan 26 2012

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

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  • Cite this

    Galdeano, C., Viayna, E., Sola, I., Formosa, X., Camps, P., Badia, A., Clos, M. V., Relat, J., Ratia, M., Bartolini, M., Mancini, F., Andrisano, V., Salmona, M., Minguillón, C., González-Muñoz, G. C., Rodríguez-Franco, M. I., Bidon-Chanal, A., Luque, F. J., & Muñoz-Torrero, D. (2012). Huprine-tacrine heterodimers as anti-amyloidogenic compounds of potential interest against Alzheimer's and prion diseases. Journal of Medicinal Chemistry, 55(2), 661-669. https://doi.org/10.1021/jm200840c