title: Clicked tacrine conjugates as acetylcholinesterase and β-amyloid directed compounds.
abstract: The multifaceted nature of Alzheimer's disease (AD) has led to the development of multi-targeted compounds based on the classical AD drug, tacrine, first known to inhibit the acetylcholine-degrading enzyme acetylcholinesterase (AChE). In the present work, we explore the potentiality of multimers of tacrine in this field. The synthesis using the so-called "click chemistry" and the in vitro study of the conjugates are described. Two or four copies of the tacrine molecule are "clicked" on a constrained cyclopeptide template proven to be a convenient tool for multimeric presentation. The multimers significantly inhibit self-induced amyloid fibril formation from Aβ(40) at low inhibitor to Aβ molar ratios at which the tacrine monomer is fully inactive (Thioflavin T assays and AFM observation). Moreover, they have the capacity to bind to Aβ(40) fibrils (SPR assays) while retaining the AChE inhibitory activity of the parent tacrine.
authors.affiliation: Département de Chimie Moléculaire (DCM), UMR CNRS/UJF 5250, ICMG-FR 2607, BP 53, 38041, Grenoble Cedex 9, France.
authors.forename: Myriam
authors.initials: M
authors.lastname: Ouberai
authors.forename: Kristoffer
authors.initials: K
authors.lastname: Brannstrom
authors.forename: Monika
authors.initials: M
authors.lastname: Vestling
authors.forename: Anders
authors.initials: A
authors.lastname: Olofsson
authors.forename: Pascal
authors.initials: P
authors.lastname: Dumy
authors.forename: Sabine
authors.initials: S
authors.lastname: Chierici
authors.forename: Julian
authors.initials: J
authors.lastname: Garcia
mesh_terms: D000110:Acetylcholinesterase / Q000378:metabolism*; D016229:Amyloid beta-Peptides / Q000037:antagonists & inhibitors* / Q000378:metabolism / Q000648:ultrastructure; D002800:Cholinesterase Inhibitors / Q000737:chemistry* / Q000494:pharmacology; D020128:Inhibitory Concentration 50; D018625:Microscopy, Atomic Force; D015394:Molecular Structure; D013619:Tacrine / Q000737:chemistry*
chemical_list: D016229:Amyloid beta-Peptides; D002800:Cholinesterase Inhibitors; D013619:Tacrine; D000110:Acetylcholinesterase