Highly potent, selective, and low cost bis-tetrahydroaminacrine inhibitors of acetylcholinesterase. Steps toward novel drugs for treating Alzheimer's disease

Yuan Ping Pang, Polly Quiram, Tanya Jelacic, Feng Hong, Stephen Brimijoin

Research output: Contribution to journalArticle

369 Scopus citations


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.

Original languageEnglish (US)
Pages (from-to)23646-23649
Number of pages4
JournalJournal of Biological Chemistry
Issue number39
StatePublished - Oct 10 1996


ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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