title: Novel huprine derivatives with inhibitory activity toward β-amyloid aggregation and formation as disease-modifying anti-Alzheimer drug candidates.
abstract: A new family of dual binding site acetylcholinesterase (AChE) inhibitors has been designed, synthesized, and tested for their ability to inhibit AChE, butyrylcholinesterase (BChE), AChE-induced and self-induced β-amyloid (Aβ) aggregation and β-secretase (BACE-1), and to cross the blood-brain barrier. The new heterodimers consist of a unit of racemic or enantiopure huprine Y or X and a donepezil-related 5,6-dimethoxy-2-[(4-piperidinyl)methyl]indane moiety as the active site and peripheral site to mid-gorge-interacting moieties, respectively, connected through a short oligomethylene linker. Molecular dynamics simulations and kinetics studies support the dual site binding to AChE. The new heterodimers are potent inhibitors of human AChE and moderately potent inhibitors of human BChE, AChE-induced and self-induced Aβ aggregation, and BACE-1, and are predicted to be able to enter the central nervous system (CNS), thus constituting promising multitarget anti-Alzheimer drug candidates with the potential to modify the natural course of this disease.
authors.affiliation: Laboratori de Química Farmacèutica (Unitat Associada al CSIC), Facultat de Farmàcia, and Institut de Biomedicina (IBUB), Universitat de Barcelona, Av. Diagonal 643, 08028, Barcelona, Spain.
authors.forename: Elisabet
authors.initials: E
authors.lastname: Viayna
authors.forename: Tània
authors.initials: T
authors.lastname: Gómez
authors.forename: Carles
authors.initials: C
authors.lastname: Galdeano
authors.forename: Lorena
authors.initials: L
authors.lastname: Ramírez
authors.forename: Míriam
authors.initials: M
authors.lastname: Ratia
authors.forename: Albert
authors.initials: A
authors.lastname: Badia
authors.forename: M Victòria
authors.initials: MV
authors.lastname: Clos
authors.forename: Ester
authors.initials: E
authors.lastname: Verdaguer
authors.forename: Félix
authors.initials: F
authors.lastname: Junyent
authors.forename: Antoni
authors.initials: A
authors.lastname: Camins
authors.forename: Mercè
authors.initials: M
authors.lastname: Pallàs
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: Mariana P
authors.initials: MP
authors.lastname: Arce
authors.forename: María 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: Pelayo
authors.initials: P
authors.lastname: Camps
authors.forename: Diego
authors.initials: D
authors.lastname: Muñoz-Torrero
mesh_terms: D000544:Alzheimer Disease / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D000634:Aminoquinolines / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000037:antagonists & inhibitors* / Q000378:metabolism; D001665:Binding Sites; D002091:Butyrylcholinesterase / Q000378:metabolism; D002800:Cholinesterase Inhibitors / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use*; D006576:Heterocyclic Compounds, 4 or More Rings / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use*; D006801:Humans; D007189:Indans / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D007700:Kinetics; D056004:Molecular Dynamics Simulation; D013329:Structure-Activity Relationship
chemical_list: D000634:Aminoquinolines; D016229:Amyloid beta-Peptides; D002800:Cholinesterase Inhibitors; D006576:Heterocyclic Compounds, 4 or More Rings; D007189:Indans; C404518:huprine X; C404519:huprine Y; D002091:Butyrylcholinesterase; D053829:Amyloid Precursor Protein Secretases