title: Highly potent, selective, and low cost bis-tetrahydroaminacrine inhibitors of acetylcholinesterase. Steps toward novel drugs for treating Alzheimer's disease.
abstract: We report highly potent, selective, and low cost bifunctional acetylcholinesterase (AChE) inhibitors developed by our two-step prototype optimization strategy utilizing computer modeling of ligand docking with target proteins: 1) identify low affinity sites normally missed by x-ray crystallography; and 2) design bifunctional analogs capable of simultaneous binding at the computer-determined low affinity site and the x-ray-identified high affinity site. Applying this strategy to 9-amino-1,2,3,4-tetrahydroacridine (THA), a drug for Alzheimer's disease, we obtained alkylene linked bis-THA analogs. These analogs were up to 10,000-fold more selective and 1,000-fold more potent than THA in inhibiting rat AChE and yet required one simple reaction to synthesize. Additionally, alkylene linked benzyl-THA analogs were developed to examine the specificity of the docking-derived low affinity THA peripheral site in AChE. The present work and our previous computational studies strongly suggest that a low affinity THA peripheral site exists in AChE. This peripheral site provides a structural basis for design of improved cholinesterase ligands for treating Alzheimer's disease and for other health-related purposes.
authors.affiliation: Neurochemistry Research, Mayo Foundation for Medical Education and Research, Jacksonville, Florida 32224, USA.
authors.forename: Y P
authors.initials: YP
authors.lastname: Pang
authors.forename: P
authors.initials: P
authors.lastname: Quiram
authors.forename: T
authors.initials: T
authors.lastname: Jelacic
authors.forename: F
authors.initials: F
authors.lastname: Hong
authors.forename: S
authors.initials: S
authors.lastname: Brimijoin
mesh_terms: D000110:Acetylcholinesterase / Q000097:blood; D000818:Animals; D001921:Brain / Q000201:enzymology; D002091:Butyrylcholinesterase / Q000378:metabolism; D002800:Cholinesterase Inhibitors / Q000737:chemistry* / Q000191:economics; D003198:Computer Simulation; D003365:Costs and Cost Analysis; D015195:Drug Design; D007700:Kinetics; D008024:Ligands; D051381:Rats; D013329:Structure-Activity Relationship; D013619:Tacrine / Q000737:chemistry* / Q000494:pharmacology
chemical_list: D002800:Cholinesterase Inhibitors; D008024:Ligands; D013619:Tacrine; D000110:Acetylcholinesterase; D002091:Butyrylcholinesterase