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New candidate drug for bipolar disorder A designed alternative to lithium shows early promise.
by Philip Ball
July 6, 2007

A potential new drug for treatment of bipolar disorder (sometimes called manic depression) is being designed by researchers in Chicago and New York. The team hopes that their compound, which works as well in mice as do the currently prescribed drugs, will ultimately provide relief without the side-effects of present treatments.

Bipolar disorder, which afflicts about 1% of adults, is typically treated with drugs called mood stabilizers, especially lithium and a compound called valproic acid. These medications can have unpleasant side effects, such as weight gain and excessive thirst, making it important to find alternatives. But although these drugs were discovered decades ago, nothing better has yet emerged.

Mood stabilizers such as lithium are thought to act by blocking the function of an enzyme called glycogen synthase kinase-3? (GSK-3?) in the brain. Researchers have found other substances that can block GSK-3? elsewhere in the body for treatment of other conditions, but these can't combat bipolar disorder because they don't get into the brain.

Tinker taylor
Alan Kozikowski of the University of Illinois in Chicago and his co-workers took a directed, rational approach to searching out a new drug candidate.

They knew about a class of newly discovered compounds that inhibit an enzyme similar to GSK-3?, and wondered whether their affinity for such enzymes meant that the compounds could bind to GSK-3? too. Tests showed that they do.

To gear this class of compounds for treating bipolar disorder, Kozikowski and colleagues did two things. First, they looked for a way to improve binding to the enzyme. Like most enzyme inhibitors, these compounds seem to stick in the enzyme's 'active site', a kind of cleft in which it binds and transforms its normal target molecules in the cell. So the researchers looked for similar molecules that might be expected to fit more neatly into this specific enzyme's cavity.

They also altered the enzyme so that it could get from the blood into the brain, which involves passing through a water-resistant membrane. "We got rid of some water-soluble groups to make them a bit greasier," says Kozikowski.

Best of the best
Using these guidelines, Kozikowski and his colleagues made a whole family of molecules (called 3-(benzofuran-3-yl)-4-(indol-3-yl)maleimides) that should act as GSK-3? inhibitors, and tested how well each of these blocked the enzyme's chemical behaviour. They identified the best of them and looked at whether it would work in animals.

In a mouse model of 'mania', hyperactive mice were calmed and moved around much less when given the new candidate drug, the researchers report in the Journal of the American Chemical Society1.

The new compound looks promising, but a lot of work remains to be done before it will be ready for human trials. One concern about GSK-3? inhibitors generally is that, if the compound disrupts functions the enzyme has elsewhere in the body, it might trigger processes that lead to cancer.

There is no evidence, however, that lithium treatment increases the risk of cancer. And Kozikowski doesn't expect such problems with his new candidates either. In fact, he has found that some related molecules show promise in stopping pancreatic cancer. The next step is to make molecules that bind as selectively to GSK-3? as possible, he adds, so that they don't interfere with the action of other, similar enzymes.

1 Kozikowski, A. P. et al. J. Am. Chem. Soc. 129 , 8328-8332 (2007).
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