Novel HCN channel inhibitors for treatment of depression
2012 Seed Grant
Dane Chetkovich, M.D., Ph.D.
Department of Neurology
Northwestern University

Existing drugs used to treat depression are mostly aimed at a set of chemicals in the brain (including serotonin), but they don’t work effectively in up to half of the patients who take them.  Dr. Chetkovich’s lab has recently made the novel discovery that a family of molecules in the brain (called HCN channels) is important for depression behaviors in mice. Specifically, they found that removing HCN channel genes lowers HCN channel activity and makes mice behave as if they are taking anti-depressants. HCN channels are also expressed in the heart, and existing drugs that block the HCN channels causes heart rhythm problems that make them not safe for trials to treat depression. Dr. Chetkovich recently uncovered a new way to block these channels only in the brain. He reasoned that finding a drug to block brain-specific HCN channels could lead to safe and totally unique treatments for depression that might work in those in whom existing treatments do not.

His 2012 Seed Grant will allow him to screen a large number of chemical compounds in a Drug Discovery compound library with the goal of finding new chemicals that block the channel function only in the brain. They will then test the effective chemicals from the screen in different studies in test tubes and live cells, in order to confirm that the compounds indeed block the function of the channels in living cells. The compounds identified in this proposal will serve as the basis for future efforts to test and design new drugs for treating depression. These drugs would hold exceptional promise for patients with difficult-to-treat depression, because they are targeting a different brain pathway than all existing treatments for depression.

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