Issue Date: March 12, 2007
Treatment For Alcohol Abuse
A new compound synthesized by Eli Lilly & Co. showed such promise in animal tests that "it should be developed for clinical use in alcoholism," according to neuroscientist Markus Heilig, clinical director at the National Institute on Alcohol Abuse & Alcoholism (NIAAA). "We're thrilled, because this has been a dream for over a decade for many of us," says Heilig, who led the team that evaluated the compound's effect in rats (J. Neurosci. 2007, 27, 2718).
Heilig found out about the compound, dubbed MTIP, when NIAAA set up a collaboration with Lilly to develop pharmacotherapies for alcoholism. Heilig's team now has tested MTIP in rats that were genetically predisposed to develop alcoholism and in rats that had been trained to be alcohol-dependent. MTIP curbed alcohol abuse in both models, "suggesting that it may be effective in treating a broad range of alcoholics," says Glenn R. Valdez of Grand Valley State University, in Allendale, Mich.
The compound inhibits binding of corticotropin-releasing factor (CRF) to the CRF1 receptor. CRF has long been established as a major regulator of stress in the body and has been linked to various psychiatric conditions, including alcoholism, Valdez explains. "Development of a CRF1 receptor antagonist has been a major goal of many pharmaceutical companies," adds Valdez, who studies the role of CRF in alcoholism. But it's been challenging to create a small-molecule antagonist that can be taken orally and enter the central nervous system, where it can reach the CRF1 receptors. The new drug, which is able to cross into the CNS, "seems to show a lot of promise," he says.
Most previous CRF1 blockers accumulate in the liver, potentially causing toxicity, Heilig says. But MTIP is markedly improved in this regard. "That's a major breakthrough in the chemistry," he notes.
Philip A. Hipskind and his team of Lilly chemists discovered MTIP when they synthesized several compounds designed to block CRF1 activity without being toxic or having other undesirable properties. Donald R. Gehlert and other Lilly colleagues then worked out the compounds' in vitro pharmacology and found that the pyridazine MTIP displayed a promising profile.
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