Researchers have developed an array of new chemicals that may attack Alzheimer's disease in a unique way. The compounds target a little understood enzyme called butyrylcholinesterase, which has recently been shown to be elevated in the brains of patients with AD.
Details about the research will appear in the Journal of Medicinal Chemistry, published by the American Chemical Society (ACS), the world's largest scientific society. The paper became available on the ACS Web May 4 and will be in the journal's May 20 print edition.
Alzheimer's disease is the fourth leading cause of death in Western countries and is a cause of severe dementia in at least four million Americans. Those over 85 years of age, the fastest growing portion of the U.S. population, have a fifty-fifty chance of developing the disease.
One characteristic of Alzheimer's disease is decreased amounts of acetylcholine, a brain signaling chemical which plays a critical role in memory processing. After doing its job, acetylcholine is normally inactivated by enzymes called cholinesterases, which come in two forms and are found throughout the body. The first, acetylcholinesterase (AChE), works at nerve endings; current Alzheimer's disease drugs aim to temporarily disable it. The role of the other form, butyrylcholinesterase (BChE), is largely unknown. "Consequently, there has been minimal interest (among drug makers) in the design, synthesis and development of butyrylcholinesterase inhibitors," says the study's co-author Nigel H. Greig, Ph.D., from the National Institute on Aging's Intramural Research Program. The Institute's Qian-sheng Yu, Ph.D., is lead author on the paper.
While some current drugs randomly inhibit both AChE and BChE, Greig says those tend to have more side effects. He adds that "the present study represents the first to develop highly selective inhibitors of BChE alone with appropriate characteristics for use in animals and humans." Recent laboratory studies have shown that BChE levels are increased in the beta-amyloid plaques which form in the brains of patients with Alzheimer's disease and that BChE amplifies plaque toxicity.
"These facts suggest," write the researchers, "that inappropriate BChE activity increases the risk and/or progression of Alzheimer's disease." What else it does, however, is unclear. People with a genetic lack of BChE activity seem to get along just fine, so scientists hope that side effects will be minimal. In fact, Greig thinks "one can inhibit BChE completely and there will not be any toxic effects," even though he says their new inhibitors do not permanently disable the enzyme.
The authors, who include University of North Carolina scientists, say preliminary studies indicate that their BChE inhibitors improve cognition and learning in rodents. They have now teamed with the newly formed biopharmaceutical company Axonyx Incorporated in New York, New York. The researchers hope, within the next 18-24 months, to develop a lead compound that can be tested in patients with Alzheimer's disease.
A nonprofit organization with a membership of nearly 159,000 chemists and chemical engineers, the American Chemical Society publishes scientific journals and databases, convenes major research conferences, and provides educational, science policy and career programs in chemistry. Its main offices are in Washington, D.C., and Columbus, Ohio.
Journal
Journal of Medicinal Chemistry