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Design, synthesis, and biological evaluation of dual binding site acetylcholinesterase inhibitors: new disease-modifying agents for Alzheimer's disease

Posted June 8th, 2010 by pschmidtke
TitleDesign, synthesis, and biological evaluation of dual binding site acetylcholinesterase inhibitors: new disease-modifying agents for Alzheimer's disease
Publication TypeJournal Article
Year of Publication2005
AuthorsMunoz-Ruiz, P, Rubio L, Garcia-Palomero E, Dorronsoro I, del Monte-Millan M, Valenzuela R, Usan P, de Austria C, Bartolini M, Andrisano V, Bidon-Chanal A, Orozco M, Luque FJ, Medina M, Martinez A
JournalJournal of medicinal chemistry
Volume48
Issue23
Pagination7223 - 7233
Date Published2005/11/17/
KeywordsAcetylcholinesterase/chemistry; Alzheimer Disease/drug therapy; Amyloid beta-Protein/antagonists & inhibitors/chemistry; Animals; Binding Sites; Butyrylcholinesterase/chemistry; Cattle; Cell Line, Molecular; Nootropic Agents/chemical synthesis/chemistry/toxicity; Protein Binding; Structure-Activity Relationship; Tacrine/analogs & derivatives/chemical synthesis/chemistry/toxicity, Tumor; Cholinesterase Inhibitors/chemical synthesis/chemistry/toxicity; Dimerization; Drug Design; Erythrocytes/enzymology; Fluorometry; Humans; Models
AbstractNew dual binding site acetylcholinesterase (AChE) inhibitors have been designed and synthesized as new potent drugs that may simultaneously alleviate cognitive deficits and behave as disease-modifying agents by inhibiting the beta-amyloid (A beta) peptide aggregation through binding to both catalytic and peripheral sites of the enzyme. Particularly, compounds 5 and 6 emerged as the most potent heterodimers reported so far, displaying IC50 values for AChE inhibition of 20 and 60 pM, respectively. More importantly, these dual AChE inhibitors inhibit the AChE-induced A beta peptide aggregation with IC50 values 1 order of magnitude lower than that of propidium, thus being the most potent derivatives with this activity reported up to date. We therefore conclude that these compounds are very promising disease-modifying agents for the treatment of Alzheimer's disease (AD).