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Neurosci."],"published-print":{"date-parts":[[2007,3,7]]},"abstract":"<jats:p>We describe a novel corticotropin-releasing factor receptor 1 (CRF<jats:sub>1<\/jats:sub>) antagonist with advantageous properties for clinical development, and its<jats:italic>in vivo<\/jats:italic>activity in preclinical alcoholism models. 3-(4-Chloro-2-morpholin-4-yl-thiazol-5-yl)-8-(1-ethylpropyl)-2,6-dimethyl-imidazo[1,2-<jats:italic>b<\/jats:italic>]pyridazine (MTIP) inhibited<jats:sup>125<\/jats:sup>I-sauvagine binding to rat pituitary membranes and cloned human CRF<jats:sub>1<\/jats:sub>with subnanomolar affinities, with no detectable activity at the CRF<jats:sub>2<\/jats:sub>receptor or other common drug targets. After oral administration to rats, MTIP inhibited<jats:sup>125<\/jats:sup>I-sauvagine binding to rat cerebellar membranes<jats:italic>ex vivo<\/jats:italic>with an ED<jats:sub>50<\/jats:sub>of \u223c1.3 mg\/kg and an oral bioavailability of 91.1%. Compared with R121919 (2,5-dimethyl-3-(6-dimethyl-4-methylpyridin-3-yl)-7-dipropylamino-pyrazolo[1,5-<jats:italic>a<\/jats:italic>]pyrimidine) and CP154526 (<jats:italic>N<\/jats:italic>-butyl-<jats:italic>N<\/jats:italic>-ethyl-4,9-dimethyl-7-(2,4,6-trimethylphenyl)-3,5,7-triazabicyclo[4.3.0]nona-2,4,8,10-tetraen-2-amine), MTIP had a markedly reduced volume of distribution and clearance. Neither open-field activity nor baseline exploration of an elevated plus-maze was affected by MTIP (1\u201310 mg\/kg). In contrast, MTIP dose-dependently reversed anxiogenic effects of withdrawal from a 3 g\/kg alcohol dose. Similarly, MTIP blocked excessive alcohol self-administration in Wistar rats with a history of dependence, and in a genetic model of high alcohol preference, the msP rat, at doses that had no effect in nondependent Wistar rats. Also, MTIP blocked reinstatement of stress-induced alcohol seeking both in postdependent and in genetically selected msP animals, again at doses that were ineffective in nondependent Wistar rats. Based on these findings, MTIP is a promising candidate for treatment of alcohol dependence.<\/jats:p>","DOI":"10.1523\/jneurosci.4985-06.2007","type":"journal-article","created":{"date-parts":[[2007,3,7]],"date-time":"2007-03-07T17:16:22Z","timestamp":1173287782000},"page":"2718-2726","source":"Crossref","is-referenced-by-count":208,"title":["3-(4-Chloro-2-Morpholin-4-yl-Thiazol-5-yl)-8-(1-Ethylpropyl)-2,6-Dimethyl-Imidazo[1,2-<i>b<\/i>]Pyridazine: A Novel Brain-Penetrant, Orally Available Corticotropin-Releasing Factor Receptor 1 Antagonist with Efficacy in Animal Models of Alcoholism"],"prefix":"10.1523","volume":"27","author":[{"given":"Donald 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