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The Journal of Neuroscience, March 7, 2007, 27(10):2718-2726; doi:10.1523/JNEUROSCI.4985-06.2007

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Behavioral/Systems/Cognitive
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

Donald R. Gehlert,¹ Andrea Cippitelli,^2,4 Annika Thorsell,² Anh Dzung Lê,³ Philip A. Hipskind,¹ Chafiq Hamdouchi,¹ Jianliang Lu,¹ Erik J. Hembre,¹ Jeffrey Cramer,¹ Min Song,¹ David McKinzie,¹ Michelle Morin,¹ Roberto Ciccocioppo,⁴ and Markus Heilig²

¹Discovery Research, Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana 46285, ²Laboratory of Clinical and Translational Studies, National Institute on Alcohol Abuse and Alcoholism–National Institutes of Health, Bethesda, Maryland 20892, ³Centre for Addiction and Mental Health, University of Toronto, Toronto, Ontario, Canada M5S 2S1, and ⁴Department of Experimental Medicine and Public Health, University of Camerino, 62032 Camerino, Italy

Correspondence should be addressed to Dr. Markus Heilig, Laboratory of Clinical and Translational Studies, National Institute on Alcohol Abuse and Alcoholism–National Institutes of Health, 10 Center Drive, 10/1-5334, Bethesda, MD 20892-1108. Email: Markus.Heilig{at}mail.nih.gov

We describe a novel corticotropin-releasing factor receptor 1 (CRF₁) antagonist with advantageous properties for clinical development, and its in vivo activity in preclinical alcoholism models. 3-(4-Chloro-2-morpholin-4-yl-thiazol-5-yl)-8-(1-ethylpropyl)-2,6-dimethyl-imidazo[1,2-b]pyridazine (MTIP) inhibited ¹²⁵I-sauvagine binding to rat pituitary membranes and cloned human CRF₁ with subnanomolar affinities, with no detectable activity at the CRF₂ receptor or other common drug targets. After oral administration to rats, MTIP inhibited ¹²⁵I-sauvagine binding to rat cerebellar membranes ex vivo with an ED₅₀ of 1.3 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-a]pyrimidine) and CP154526 (N-butyl-N-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 (1–10 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.

Key words: alcoholism; drug seeking; self-administration; relapse; stress; CRF

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Received Nov. 16, 2006; revised Dec. 23, 2006; accepted Jan. 21, 2007.

Correspondence should be addressed to Dr. Markus Heilig, Laboratory of Clinical and Translational Studies, National Institute on Alcohol Abuse and Alcoholism–National Institutes of Health, 10 Center Drive, 10/1-5334, Bethesda, MD 20892-1108. Email: Markus.Heilig{at}mail.nih.gov

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