Search: WFRF:(Lu Jianliang)
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3-(4-Chloro-2-morph...
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. (author)
- Eli Lilly and Company, Indianapolis, IN, USA
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- Cippitelli, Andrea (author)
- National Institute on Alcohol Abuse and Alcoholism, NIH; Bethesda, MD, USA
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- Thorsell, Annika (author)
- National Institute on Alcohol Abuse and Alcoholism, NIH; Bethesda, MD, USA
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- Lê, Anh Dzung (author)
- University of Toronto, Canada
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- Hipskind, Philip A (author)
- Eli Lilly and Company, Indianapolis, IN, USA
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- Hamdouchi, Chafiq (author)
- Eli Lilly and Company, Indianapolis, IN, USA
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- Lu, Jianliang (author)
- Eli Lilly and Company, Indianapolis, IN, USA
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- Hembre, Erik J. (author)
- Eli Lilly and Company, Indianapolis, IN, USA
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- Cramer, Jeffrey (author)
- Eli Lilly and Company, Indianapolis, IN, USA
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- Song, Min (author)
- Eli Lilly and Company, Indianapolis, IN, USA
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- McKinzie, David (author)
- Eli Lilly and Company, Indianapolis, IN, USA
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- Morin, Michelle (author)
- Eli Lilly and Company, Indianapolis, IN, USA
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- Ciccocioppo, Roberto (author)
- University of Camerino, Italy
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- Heilig, Markus (author)
- National Institute on Alcohol Abuse and Alcoholism, NIH; Bethesda, MD, USA
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(creator_code:org_t)
- Society for Neuroscience, 2007
- 2007
- English.
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In: Journal of Neuroscience. - : Society for Neuroscience. - 0270-6474 .- 1529-2401. ; 27:10, s. 2718-2726
- Related links:
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https://urn.kb.se/re...
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https://doi.org/10.1...
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Abstract
Subject headings
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- 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
- MEDICIN OCH HÄLSOVETENSKAP -- Medicinska och farmaceutiska grundvetenskaper -- Neurovetenskaper (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Basic Medicine -- Neurosciences (hsv//eng)
Keyword
- alcoholism; drug seeking; self-administration; relapse; stress; CRF
Publication and Content Type
- ref (subject category)
- art (subject category)
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- By the author/editor
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Gehlert, Donald ...
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Cippitelli, Andr ...
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Thorsell, Annika
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Lê, Anh Dzung
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Hipskind, Philip ...
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Hamdouchi, Chafi ...
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show more...
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Lu, Jianliang
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Hembre, Erik J.
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Cramer, Jeffrey
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Song, Min
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McKinzie, David
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Morin, Michelle
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Ciccocioppo, Rob ...
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Heilig, Markus
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- About the subject
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- MEDICAL AND HEALTH SCIENCES
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MEDICAL AND HEAL ...
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and Basic Medicine
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and Neurosciences
- Articles in the publication
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Journal of Neuro ...
- By the university
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Linköping University