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Inhibition of Human Cholinesterases by Drugs Used to Treat Alzheimer Disease

Darvesh, Sultan*†‡§; Walsh, Ryan†‡; Kumar, Rohit; Caines, Angela; Roberts, Sheila; Magee, David§; Rockwood, Kenneth*; Martin, Earl

Alzheimer Disease & Associated Disorders: April 2003 - Volume 17 - Issue 2 - p 117–126

Current approaches to the treatment of cognitive and behavioral symptoms of Alzheimer disease emphasize the use of cholinesterase inhibitors. The kinetic effects of the cholinesterase inhibitors donepezil, galantamine, metrifonate, physostigmine, rivastigmine, and tetrahydroaminoacridine were examined with respect to their action on the esterase and aryl acylamidase activities of human acetylcholinesterase (AChE) and human butyrylcholinesterase (BuChE). Each of these drugs inhibited both AChE and BuChE, but to different degrees. Inhibition of BuChE by these compounds was approximately the same, or better, when acetylthiocholine, the analog of the neurotransmitter acetylcholine, was used as the substrate, instead of butyrylthiocholine. In addition, for these drugs, the inhibition of aryl acylamidase activity paralleled that observed for inhibition of esterase activity of AChE and BuChE. Given that drugs that are currently in use for the treatment of Alzheimer disease inhibit both AChE and BuChE, the development of drugs targeted toward the exclusive inhibition of one or the other cholinesterase may be important for understanding the relative importance of inhibition of BuChE and AChE in the treatment of this disease.

* From the Departments of Medicine (Neurology and Geriatric Medicine) and

Anatomy and Neurobiology, Dalhousie University, Halifax, Nova Scotia; the

Department of Chemistry, Mount Saint Vincent University, Halifax, Nova Scotia; and the

§ Department of Chemistry, University of New Brunswick, Fredericton, New Brunswick, Canada.

Received June 17, 2002. Accepted December 26, 2002.

Supported by Dalhousie University Internal Medicine Research Fund, Queen Elizabeth II Health Science Center Research Fund, Heart and Stroke Foundation of New Brunswick, the Committee on Research and Publications of Mount Saint Vincent University, and National Sciences and Engineering Research Council of Canada Undergraduate Student Research Award. Dr. Rockwood is supported by the Dalhousie Medical Research Fund as Kathryn Allen Weldon Professor of Alzheimer Research, and by an Investigator Award from the Canadian Institutes of Health Research.

Address correspondence and reprint requests to Sultan Darvesh, M.D., Ph.D., F.R.C.P.C., QEII Health Sciences Center, Camp Hill Veterans' Memorial, 5955 Veterans' Memorial Lane, Halifax, Nova Scotia, B3H 2E1, Canada. E-mail:

© 2003 Lippincott Williams & Wilkins, Inc.