title: Dual binding site acetylcholinesterase inhibitors: potential new disease-modifying agents for AD.
abstract: The therapeutic potential of acetylcholinesterase (AChE) inhibitors has been strengthened recently by evidence showing that besides their role in cognitive function, they might contribute to slow down the neurodegeneration in Alzheimer's disease (AD) patients. It is known that AChE exerts secondary noncholinergic functions, related to its peripheral anionic site, in cell adhesion and differentiation, and recent findings also support its role in mediating the processing and deposition of beta-amyloid (Abeta) peptide. AChE is one of the proteins that colocalizes with Abeta peptide deposits in the brain of AD patients and promotes Abeta fibrillogenesis by forming stable AChEA beta complexes. Additionally, it has also been postulated that AChE binds through its peripheral site to the Abeta nonamyloidogenic form and acts as a pathological chaperone inducing a conformational transition to the amyloidogenic form (Inestrosa et al., 1996; Bartolini et al., 2003). Anew series of dual binding site AChE inhibitors has been designed and synthesized as new potent AChE inhibitors, which might simultaneously alleviate cognitive deficits and behave as disease-modifying agents by inhibiting Abeta peptide aggregation through binding to both catalytic and peripheral sites of the enzyme.
authors.affiliation: Neuropharma, S.A., 28760 Tres Cantos, Madrid, Spain.
authors.forename: María
authors.initials: M
authors.lastname: del Monte-Millán
authors.forename: Esther
authors.initials: E
authors.lastname: García-Palomero
authors.forename: Rita
authors.initials: R
authors.lastname: Valenzuela
authors.forename: Paola
authors.initials: P
authors.lastname: Usán
authors.forename: Celia
authors.initials: C
authors.lastname: de Austria
authors.forename: Pilar
authors.initials: P
authors.lastname: Muñoz-Ruiz
authors.forename: Laura
authors.initials: L
authors.lastname: Rubio
authors.forename: Isabel
authors.initials: I
authors.lastname: Dorronsoro
authors.forename: Ana
authors.initials: A
authors.lastname: Martínez
authors.forename: Miguel
authors.initials: M
authors.lastname: Medina
mesh_terms: D000110:Acetylcholinesterase / Q000378:metabolism; D000544:Alzheimer Disease / Q000188:drug therapy* / Q000201:enzymology; D002800:Cholinesterase Inhibitors / Q000493:pharmacokinetics* / Q000627:therapeutic use*; D006801:Humans; D007700:Kinetics; D013619:Tacrine / Q000031:analogs & derivatives / Q000493:pharmacokinetics
chemical_list: C098212:6-chlorotacrine; D002800:Cholinesterase Inhibitors; D013619:Tacrine; D000110:Acetylcholinesterase