Discovery of Aminobenzyloxyarylamides as 魏 Opioid Receptor Selective Antagonists: Application to Preclinical Development of a 魏 Opioid Receptor Antagonist Receptor Occupancy Tracer

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• 作者：Charles H. Mitch ; Steven J. Quimby ; Nuria Diaz ; Concepcion Pedregal ; Marta G. de la Torre ; Alma Jimenez ; Qing Shi ; Emily J. Canada ; Steven D. Kahl ; Michael A. Statnick ; David L. McKinzie ; Dana R. Benesh ; Karen S. Rash ; Vanessa N. Barth
• 刊名：Journal of Medicinal Chemistry
• 出版年：2011
• 出版时间：December 8, 2011
• 年：2011
• 卷：54
• 期：23
• 页码：8000-8012
• 全文大小：992K
• 年卷期：v.54,no.23(December 8, 2011)
• ISSN：1520-4804

文摘

Arylphenylpyrrolidinylmethylphenoxybenzamides were found to have high affinity and selectivity for 魏 opioid receptors. On the basis of receptor binding assays in Chinese hamster ovary (CHO) cells expressing cloned human opioid receptors, (S)-3-fluoro-4-(4-((2-(3-fluorophenyl)pyrrolidin-1-yl)methyl)phenoxy)benzamide (25) had a K_i = 0.565 nM for 魏 opioid receptor binding while having a K_i = 35.8 nM for 渭 opioid receptors and a K_i = 211 nM for 未 opioid receptor binding. Compound 25 was also a potent antagonist of 魏 opioid receptors when tested in vitro using a [³⁵S]-guanosine 5鈥?i>O-[3-thiotriphosphate] ([³⁵S]GTP-纬-S) functional assay in CHO cells expressing cloned human opioid receptors. Compounds were also evaluated for potential use as receptor occupancy tracers. Tracer evaluation was done in vivo, using liquid chromatography-tandem mass spectrometry (LC/MS/MS) methods, precluding the need for radiolabeling. (S)-3-Chloro-4-(4-((2-(pyridine-3-yl)pyrrolidin-1-yl)methyl)phenoxy)benzamide (18) was found to have favorable properties for a tracer for receptor occupancy, including good specific versus nonspecific binding and good brain uptake.