title: Tacrine-based dual binding site acetylcholinesterase inhibitors as potential disease-modifying anti-Alzheimer drug candidates.
abstract: Two novel families of dual binding site acetylcholinesterase (AChE) inhibitors have been developed, consisting of a tacrine or 6-chlorotacrine unit as the active site interacting moiety, either the 5,6-dimethoxy-2-[(4-piperidinyl)methyl]-1-indanone fragment of donepezil (or the indane derivative thereof) or a 5-phenylpyrano[3,2-c]quinoline system, reminiscent to the tryciclic core of propidium, as the peripheral site interacting unit, and a linker of suitable length as to allow the simultaneous binding at both sites. These hybrid compounds are all potent and selective inhibitors of human AChE, and more interestingly, are able to interfere in vitro both formation and aggregation of the beta-amyloid peptide, the latter effects endowing these compounds with the potential to modify Alzheimer's disease progression.
authors.affiliation: Laboratori de Química Farmacèutica (Unitat Associada al CSIC), Facultat de Farmàcia, and Institut de Biomedicina (IBUB), Universitat de Barcelona, Av. Diagonal 643, E-08028 Barcelona, Spain.
authors.forename: Pelayo
authors.initials: P
authors.lastname: Camps
authors.forename: Xavier
authors.initials: X
authors.lastname: Formosa
authors.forename: Carles
authors.initials: C
authors.lastname: Galdeano
authors.forename: Tània
authors.initials: T
authors.lastname: Gómez
authors.forename: Diego
authors.initials: D
authors.lastname: Muñoz-Torrero
authors.forename: Lorena
authors.initials: L
authors.lastname: Ramírez
authors.forename: Elisabet
authors.initials: E
authors.lastname: Viayna
authors.forename: Elena
authors.initials: E
authors.lastname: Gómez
authors.forename: Nicolás
authors.initials: N
authors.lastname: Isambert
authors.forename: Rodolfo
authors.initials: R
authors.lastname: Lavilla
authors.forename: Albert
authors.initials: A
authors.lastname: Badia
authors.forename: M Victòria
authors.initials: MV
authors.lastname: Clos
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: Axel
authors.initials: A
authors.lastname: Bidon-Chanal
authors.forename: Oscar
authors.initials: O
authors.lastname: Huertas
authors.forename: Thomai
authors.initials: T
authors.lastname: Dafni
authors.forename: F Javier
authors.initials: FJ
authors.lastname: Luque
mesh_terms: D000110:Acetylcholinesterase / Q000737:chemistry* / Q000378:metabolism*; D000544:Alzheimer Disease / Q000188:drug therapy* / Q000453:epidemiology; D020816:Amino Acid Motifs; D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors; D016229:Amyloid beta-Peptides / Q000737:chemistry / Q000378:metabolism; D016282:Aspartic Acid Endopeptidases / Q000037:antagonists & inhibitors; D020134:Catalytic Domain; D002800:Cholinesterase Inhibitors / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D000077265:Donepezil; D055808:Drug Discovery; D006801:Humans; D007189:Indans / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D008958:Models, Molecular; D010880:Piperidines / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D055503:Protein Multimerization / Q000187:drug effects; D020836:Protein Structure, Quaternary; D011804:Quinolines / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D013619:Tacrine / Q000737:chemistry* / Q000494:pharmacology* / Q000627:therapeutic use
chemical_list: D016229:Amyloid beta-Peptides; D002800:Cholinesterase Inhibitors; D007189:Indans; D010880:Piperidines; D011804:Quinolines; D013619:Tacrine; D000077265:Donepezil; C037219:quinoline; D000110:Acetylcholinesterase; D053829:Amyloid Precursor Protein Secretases; D016282:Aspartic Acid Endopeptidases; C509280:BACE1 protein, human