Cholinesterase Inhibitors:  Xanthostigmine Derivatives Blocking the Acetylcholinesterase-Induced β-Amyloid Aggregation

• Published in: Journal of medicinal chemistry Vol. 48; no. 13; pp. 4444 - 4456
• Main Authors: Belluti, Federica, Rampa, Angela, Piazzi, Lorna, Bisi, Alessandra, Gobbi, Silvia, Bartolini, Manuela, Andrisano, Vincenza, Cavalli, Andrea, Recanatini, Maurizio, Valenti, Piero
• Format: Journal Article
• Language: English
• Published: Washington, DC American Chemical Society 30-06-2005
• Subjects: Acetylcholinesterase - chemistry; Acetylcholinesterase - metabolism; Amyloid beta-Peptides - chemistry; Amyloid beta-Peptides - drug effects; Amyloid beta-Peptides - metabolism; Binding Sites; Biological and medical sciences; Butyrylcholinesterase - chemistry; Butyrylcholinesterase - metabolism; Carbamates - chemical synthesis; Carbamates - chemistry; Carbamates - pharmacology; Cholinesterase Inhibitors - chemical synthesis; Cholinesterase Inhibitors - chemistry; Cholinesterase Inhibitors - pharmacology; Kinetics; Medical sciences; Models, Molecular; Molecular Structure; Neuropharmacology; Pharmacology. Drug treatments; Protein Conformation; Psychoanaleptics: cns stimulant, antidepressant agent, nootropic agent, mood stabilizer..., (alzheimer disease); Psychology. Psychoanalysis. Psychiatry; Psychopharmacology; Structure-Activity Relationship; Esterases; Acetylcholinesterase; Oxygen heterocycle; Organic carbamate; Chlorine Organic compounds; Bicyclic compound; Molecular aggregation; Aromatic compound; Anticholinesterase agent; Inhibition; Human; Indan derivatives; Enzyme; Benzene derivatives; Enzyme inhibitor; Aminoether; Antialzheimer agent; Tricyclic compound; Anthracene derivatives; Condensed benzenic compound; In vitro; Naphthalene derivatives; Carboxylic ester hydrolases; β Amyloid protein; Hydrolases; Benzofuran derivatives; Enone
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm049515h

In continuing research that led us to identify a new class of carbamate derivatives acting as potent (Rampa et al. J. Med. Chem. 1998, 41, 3976) and long-lasting (Rampa et al. J. Med. Chem. 2001, 44, 3810) acetylcholinesterase (AChE) inhibitors, we obtained some analogues able to simultaneously block both the catalytic and the β-amyloid (Aβ) proaggregatory activities of AChE. The key feature of these derivatives is a 2-arylidenebenzocycloalkanone moiety that provides the ability to bind at the AChE peripheral site responsible for promoting the Aβ aggregation. The new carbamates were tested in vitro for the inhibition of both cholinesterases and also for the ability to prevent the AChE-induced Aβ aggregation. All of the compounds had AChE IC50 values in the nanomolar range and showed the ability to block the AChE-induced Aβ aggregation, thus supporting the feasibility of this new strategy in the search of compounds for the treatment of Alzheimer's disease.