کد مقاله | کد نشریه | سال انتشار | مقاله انگلیسی | نسخه تمام متن |
---|---|---|---|---|
2014008 | 1067139 | 2008 | 14 صفحه PDF | دانلود رایگان |
عنوان انگلیسی مقاله ISI
MPZP: A novel small molecule corticotropin-releasing factor type 1 receptor (CRF1) antagonist
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کلمات کلیدی
موضوعات مرتبط
علوم زیستی و بیوفناوری
بیوشیمی، ژنتیک و زیست شناسی مولکولی
زیست شیمی
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چکیده انگلیسی
The extrahypothalamic stress peptide corticotropin-releasing factor (CRF) system is an important regulator of behavioral responses to stress. Dysregulation of CRF and the CRF type 1 receptor (CRF1) system is hypothesized to underlie many stress-related disorders. Modulation of the CRF1 system by non-peptide antagonists currently is being explored as a therapeutic approach for anxiety disorders and alcohol dependence. Here, we describe a new, less hydrophilic (cLogP â¼Â 2.95), small molecule, non-peptide CRF1 antagonist with high affinity (Ki = 4.9 nM) and specificity for CRF1 receptors: N,N-bis(2-methoxyethyl)-3-(4-methoxy-2-methylphenyl)-2,5-dimethyl-pyrazolo[1,5-a] pyrimidin-7-amine (MPZP). The compound was systemically administered to adult male rats in two behavioral models dependent on the CRF1 system: defensive burying (0, 5, 20 mg/kg, n = 6-11 for each dose) and alcohol dependence (0, 5, 10, 20 mg/kg, n = 8 for each self-administration group). Acute administration of MPZP reduced burying behavior in the defensive burying model of active anxiety-like behavior. MPZP also attenuated withdrawal-induced excessive drinking in the self-administration model of alcohol dependence without affecting nondependent alcohol drinking or water consumption. The present findings support the proposed significance of the CRF1 system in anxiety and alcohol dependence and introduce a promising new compound for further development in the treatment of alcohol dependence and stress-related disorders.
ناشر
Database: Elsevier - ScienceDirect (ساینس دایرکت)
Journal: Pharmacology Biochemistry and Behavior - Volume 88, Issue 4, February 2008, Pages 497-510
Journal: Pharmacology Biochemistry and Behavior - Volume 88, Issue 4, February 2008, Pages 497-510
نویسندگان
Heather N. Richardson, Yu Zhao, Ãva M. Fekete, Cindy K. Funk, Peter Wirsching, Kim D. Janda, Eric P. Zorrilla, George F. Koob,