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Nov/Dec 2000
Vol. 3, No. 9, p. 18.

news in brief

Brain booster surprise

Figure 1. Schematic representation of Caco-2 permeablility assay.

More than AChE?.

With the discovery of acylpeptide hydrolase, U.K. researchers believe that there may be more to the buildup of acetylcholine (ACh) than inhibited acetylcholine esterase (AChE).

A surprising discovery by U.K. researchers could lead to cognition-enhancing drugs based on the action of organophosphorus compounds on a novel target in the brain.

Organophosphorus compounds inhibit acetylcholinesterase (AChE), leading to a buildup of the neurotransmitter acetylcholine, which is thought to enhance cognition in Alzheimer’s disease. But Paul Richards and his colleagues at the University of Leicester (Leicester, U.K.) believe that the observed effects of AChE inhibitors might in part be due to the inhibition of a second target. Because some organophosphorus compounds do not improve cognition in laboratory animals, and the lowest effective doses do not correspond to the minimum concentration required for AChE inhibition, they believe that additional, unintended targets contribute to the observed benefits.

The researchers recently identified a new target for organophosphorus compounds, acylpeptide hydrolase (Mol. Pharmacol. 2000, 58, 577–583). Although the compound’s normal function remains unclear, it is strongly inhibited by various organophosphorus compounds at levels 6–10 times lower than those required by AChE. This makes it potentially useful as a target for organophosphorus drugs or as a toxicological indicator.

Organophosphorus compounds have traditionally been associated with esterase inhibition, so the finding that a peptidase is also a target has come as a surprise. It also has serious pharmacological implications because one of the experimental drugs for treating Alzheimer’s disease, metrifonate, is based on dichlorvos and was selected for its AChE inhibitory activity. That the parent dichlorvos has a far greater effect on acylpeptide hydrolase implies that its design for AChE was perhaps misguided.

“Our current work is directed at discovering the identity of the natural peptide substrates for acylpeptide hydrolase in the brain,” said Richards. “If we can do this, then we will have a complete hypothesis to explain the noncholinergic component of cognitive enhancement.”

DAVID BRADLEY

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