Di‐n‐Butyl 2‐Chlorophenyl Phosphate: A Potential Therapeutic for Alzheimer's Disease

Abstract

Alzheimer's Disease (AD) is characterized by decreased levels of acetylcholine and formation of neurotoxic β‐amyloid plaque. The result is a loss of cognitive function. Both effects correlate with elevated levels of butyrylcholinesterase (BuChE) activity. Reversible cholinesterase inhibitors have been shown to decrease β‐amyloid peptide formation in animal models. We have shown that aryl dialkyl phosphates are potent and highly selective irreversible inhibitors of BuChE. In this study, the toxicity of di‐n‐butyl 2‐chlorophenyl phosphate (DB2ClPP) was determined in cultured human SK‐N‐SH neuroblastoma cells. Cells were exposed to increasing concentrations of DB2ClPP for 24 hrs and then assayed for changes in cell proliferation, membrane integrity, and induction of apoptosis. Concentrations of DB2ClPP as high as 10 μM had no effect on any of these parameters. Incubation of whole blood with DB2ClPP revealed that the compound is present at detectable levels in plasma after 1 hr. These studies suggest that there is a significant potential for this class of compounds as a therapeutic to treat the symptoms of AD.