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Volume 271, Number 39, Issue of September 27, 1996 pp. 23646-23649
©1996 by The American Society for Biochemistry and Molecular Biology, Inc.

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COMMUNICATION:
Highly Potent, Selective, and Low Cost Bis-tetrahydroaminacrine Inhibitors of Acetylcholinesterase
STEPS TOWARD NOVEL DRUGS FOR TREATING ALZHEIMER'S DISEASE

(Received for publication, May 29, 1996, and in revised form, July 15, 1996)

Yuan-Ping Pang , Polly Quiram ^¶ , Tanya Jelacic ^¶ , Feng Hong and Stephen Brimijoin ^¶

From  Neurochemistry Research, Mayo Foundation for Medical Education and Research, Jacksonville, Florida 32224 and the ^¶ Department of Pharmacology, Mayo Foundation for Medical Education and Research, Rochester, Minnesota 55905

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.

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