title: Huprine-tacrine heterodimers as anti-amyloidogenic compounds of potential interest against Alzheimer's and prion diseases.
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.
authors.affiliation: Laboratori de Química Farmacèutica (Unitat Associada al CSIC), Facultat de Farmàcia, Universitat de Barcelona, Av. Diagonal 643, E-08028 Barcelona, Spain.
authors.forename: Carles
authors.initials: C
authors.lastname: Galdeano
authors.forename: Elisabet
authors.initials: E
authors.lastname: Viayna
authors.forename: Irene
authors.initials: I
authors.lastname: Sola
authors.forename: Xavier
authors.initials: X
authors.lastname: Formosa
authors.forename: Pelayo
authors.initials: P
authors.lastname: Camps
authors.forename: Albert
authors.initials: A
authors.lastname: Badia
authors.forename: M Victòria
authors.initials: MV
authors.lastname: Clos
authors.forename: Júlia
authors.initials: J
authors.lastname: Relat
authors.forename: Míriam
authors.initials: M
authors.lastname: Ratia
authors.forename: Manuela
authors.initials: M
authors.lastname: Bartolini
authors.forename: Francesca
authors.initials: F
authors.lastname: Mancini
authors.forename: Vincenza
authors.initials: V
authors.lastname: Andrisano
authors.forename: Mario
authors.initials: M
authors.lastname: Salmona
authors.forename: Cristina
authors.initials: C
authors.lastname: Minguillón
authors.forename: Gema C
authors.initials: GC
authors.lastname: González-Muñoz
authors.forename: M Isabel
authors.initials: MI
authors.lastname: Rodríguez-Franco
authors.forename: Axel
authors.initials: A
authors.lastname: Bidon-Chanal
authors.forename: F Javier
authors.initials: FJ
authors.lastname: Luque
authors.forename: Diego
authors.initials: D
authors.lastname: Muñoz-Torrero
mesh_terms: D000110:Acetylcholinesterase / Q000737:chemistry / Q000378:metabolism; D000544:Alzheimer Disease / Q000188:drug therapy*; D000634:Aminoquinolines / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D016229:Amyloid beta-Peptides / Q000037:antagonists & inhibitors* / Q000737:chemistry; D000818:Animals; D001921:Brain / Q000378:metabolism; D002091:Butyrylcholinesterase / Q000737:chemistry; D002800:Cholinesterase Inhibitors / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D006576:Heterocyclic Compounds, 4 or More Rings / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D006801:Humans; D008567:Membranes, Artificial; D051379:Mice; D008958:Models, Molecular; D010446:Peptide Fragments / Q000037:antagonists & inhibitors / Q000737:chemistry; D010539:Permeability; D017096:Prion Diseases / Q000188:drug therapy*; D011328:Prions / Q000037:antagonists & inhibitors* / Q000737:chemistry; D011994:Recombinant Proteins / Q000737:chemistry; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D013619:Tacrine / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology
chemical_list: D000634:Aminoquinolines; D016229:Amyloid beta-Peptides; D002800:Cholinesterase Inhibitors; D006576:Heterocyclic Compounds, 4 or More Rings; D008567:Membranes, Artificial; D010446:Peptide Fragments; D011328:Prions; D011994:Recombinant Proteins; C404519:huprine Y; D013619:Tacrine; D000110:Acetylcholinesterase; D002091:Butyrylcholinesterase