Corticotropin-releasing factor (CRF; also known as CRH) — a peptide hormone with a well-established role in stress — has attracted considerable attention as a therapeutic target for disorders such as anxiety and depression. Writing in the Journal of Neuroscience, Heilig and colleagues 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 extrahypothalamic CRF are observed after acute alcohol withdrawal and prolonged alcohol exposure. Indeed, CRF antagonists have been shown to reduce the anxiogenic effects of alcohol withdrawal and ameliorate some of the symptoms of alcohol dependence, 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 barrier 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 withdrawal 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, without affecting alcohol metabolism or CRF activity under normal circumstances, 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.