Scientists Discover Structure of Pain-Modulating Enzyme

In a new study, scientists have solved the structure of an enzyme that modulates central nervous system (CNS) functions such as pain perception, cognition, feeding, sleep, and locomotor activity. They suggest that a specific inhibitor to this enzyme might provide pain relief without any side effects. The study was published in the November 20, 2002, issue of Science.

The enzyme, called fatty acid amid hydrolase (FAAH), breaks down certain fatty signaling molecules that reside in the lipid membranes of the CNS cells. The FAAH modulates the action of these molecules through an unusual mechanism whereby it scoops them out of the cell membranes and chews them up.

FAAH is an attractive target for pain therapy because its inhibition would increase the longevity of anandamide, an endogenous cannabinoid released by the body when it senses pain, by preventing its breakdown and allowing it to continue providing some natural pain relief. The structure of FAAH could form a template for designing specific inhibitors that control the action of FAAH when the body senses pain, conclude the researchers, from The Scripps Research Institute (TSRI, La Jolla, CA, USA).

"As soon as we had the view of the active site, we knew FAAH could be used to make lead clinical candidates,” said Raymond Stevens, a professor in the department of molecular biology and chemistry at TSRI and the lead author. "The deep pocket with well-defined cavities provides the guidance to take the currently available tight binding inhibitors and improve on their specificity and pharmakokinetic properties.”




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