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

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Gehlert, Donald R.Eli Lilly and Company, Indianapolis, IN, USA (author)

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

Article/chapterEnglish2007

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Society for Neuroscience,2007
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LIBRIS-ID:oai:DiVA.org:liu-101855
https://urn.kb.se/resolve?urn=urn:nbn:se:liu:diva-101855URI
https://doi.org/10.1523/JNEUROSCI.4985-06.2007DOI

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Language:English
Summary in:English

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Notes

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 approximately 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.

Subject headings and genre

MEDICIN OCH HÄLSOVETENSKAP Medicinska och farmaceutiska grundvetenskaper Neurovetenskaper hsv//swe
MEDICAL AND HEALTH SCIENCES Basic Medicine Neurosciences hsv//eng
alcoholism; drug seeking; self-administration; relapse; stress; CRF

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Cippitelli, AndreaNational Institute on Alcohol Abuse and Alcoholism, NIH; Bethesda, MD, USA (author)
Thorsell, AnnikaNational Institute on Alcohol Abuse and Alcoholism, NIH; Bethesda, MD, USA(Swepub:liu)annth96 (author)
Lê, Anh DzungUniversity of Toronto, Canada (author)
Hipskind, Philip AEli Lilly and Company, Indianapolis, IN, USA (author)
Hamdouchi, ChafiqEli Lilly and Company, Indianapolis, IN, USA (author)
Lu, JianliangEli Lilly and Company, Indianapolis, IN, USA (author)
Hembre, Erik J.Eli Lilly and Company, Indianapolis, IN, USA (author)
Cramer, JeffreyEli Lilly and Company, Indianapolis, IN, USA (author)
Song, MinEli Lilly and Company, Indianapolis, IN, USA (author)
McKinzie, DavidEli Lilly and Company, Indianapolis, IN, USA (author)
Morin, MichelleEli Lilly and Company, Indianapolis, IN, USA (author)
Ciccocioppo, RobertoUniversity of Camerino, Italy (author)
Heilig, MarkusNational Institute on Alcohol Abuse and Alcoholism, NIH; Bethesda, MD, USA(Swepub:liu)marhe41 (author)
Eli Lilly and Company, Indianapolis, IN, USANational Institute on Alcohol Abuse and Alcoholism, NIH; Bethesda, MD, USA (creator_code:org_t)

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In:Journal of Neuroscience: Society for Neuroscience27:10, s. 2718-27260270-64741529-2401

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By the author/editor: Gehlert, Donald ...; Cippitelli, Andr ...; Thorsell, Annika; Lê, Anh Dzung; Hipskind, Philip ...; Hamdouchi, Chafi ...; show more...; Lu, Jianliang; Hembre, Erik J.; Cramer, Jeffrey; Song, Min; McKinzie, David; Morin, Michelle; Ciccocioppo, Rob ...; Heilig, Markus; show less...

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MEDICAL AND HEALTH SCIENCES: MEDICAL AND HEAL ...; and Basic Medicine; and Neurosciences

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