DOI:10.1038/nrd2318 Corticotropin-releasing factor (CRF;

also known as CRH) — a peptide hormone with a well-established role in stress — has attracted consider-able attention as a therapeutic target for disorders such as anxiety and depression. Writing in the Journal

of Neuroscience, Heilig and col-leagues now describe the effects of a novel, brain-penetrant CRF1 receptor antagonist developed by Philip Hipskind and his team of chemists at Eli Lilly, MTIP (3-(4-chloro-2-morpholin-4-yl-thiazol-5-yl)-8-(1-ethylpropyl)-2,6-dimethyl-imidazo[1,2-b]pyridazine), which holds promise for the treatment of alcohol dependence.

Elevated levels of extrahypotha-lamic CRF are observed after acute alcohol withdrawal and pro-longed alcohol exposure. Indeed, CRF antagonists have been shown to reduce the anxiogenic effects of alco-hol withdrawal and ameliorate some of the symptoms of alcohol depend-ence, such as excessive alcohol self-administration and stress-induced relapse to alcohol seeking in rats. However, difficulties in discovering orally available CRF antagonists that are able to cross the blood–brain bar-

rier have hindered the translation of these findings to the clinic.

MTIP, a pyridazine-based compound, showed high affinity and selectivity for human CRF1 receptors in vitro and inhibited CRF-induced cyclic AMP

formation in cells overexpressing this receptor. Oral administration

of MTIP prevented 125I-sauvagine, a high-affinity radioligand for CRF1 receptors, from binding to rat cerebellar homogenates ex vivo.

In behavioural studies, MTIP reduced the anxiogenic effect

of acute alcohol withdrawal in alcohol-naive rats, as measured by percentage ‘open time’ in an elevated plus-maze, without affecting normal locomotive behaviour or causing toxicity. MTIP also suppressed the self-administration of alcohol in Marchegian Sardinian rats, which are genetically predisposed to develop alcoholism, and in rats with a history of alcohol dependence (put through several cycles of heavy alcohol consumption and with-drawal to create dependency) in a dose-dependent manner. Moreover, administration of MTIP eliminated their susceptibility to relapse under stress induced by footshock.

The ability of MTIP to reduce the anxiogenic effects of acute alcohol withdrawal, excessive alcohol self-administration and stress-induced relapse in predisposed animals, with-out affecting alcohol metabolism or CRF activity under normal circum-stances, suggests that MTIP could prove to be useful for the treatment of alcoholism. Furthermore, the desirable physicochemical properties of MTIP mean that it could also have potential for treating other stress-related disorders in which CRF is upregulated.

Monica Hoyos Flight

ORIGINAL RESEARCH PAPER Gehlert, D. R.

et al. 3-(4-chloro-2-morpholin-4-yl-thiazol-5-yl)-

8-(1-ethylpropyl)-2,6-dimethyl-imidazo[1,2-b]

pyridazine: a novel brain-penetrant, orally

available corticotropin-releasing factor receptor 1

antagonist with efficacy in animal models of

alcoholism. J. Neurosci. 27, 2718–2726 (2007)

A D D I C T I O N

Cutting down alcohol consumption

R E S E A R C H H I G H L I G H T S

NATURE REVIEWS | DRUG DISCOVERY VOLUME 6 | MAY 2007

© 2007 Nature Publishing Group