Discovery of a Selective and CNS Penetrant Negative Allosteric Modulator of Metabotropic Glutamate Receptor Subtype 3 with Antidepressant and Anxiolytic Activity in Rodents

详细信息    查看全文

• 作者：Julie L. Engers ; Alice L. Rodriguez ; Leah C. Konkol ; Ryan D. Morrison ; Analisa D. Thompson ; Frank W. Byers ; Anna L. Blobaum ; Sichen Chang ; Daryl F. Venable ; Matthew T. Loch ; Colleen M. Niswender ; J. Scott Daniels ; Carrie K. Jones ; P. Jeffrey Conn ; Craig W. Lindsley ; Kyle A. Emmitte
• 刊名：Journal of Medicinal Chemistry
• 出版年：2015
• 出版时间：September 24, 2015
• 年：2015
• 卷：58
• 期：18
• 页码：7485-7500
• 全文大小：610K
• ISSN：1520-4804

文摘

Previous preclinical work has demonstrated the therapeutic potential of antagonists of the group II metabotropic glutamate receptors (mGlus). Still, compounds that are selective for the individual group II mGlus (mGlub>2b> and mGlub>3b>) have been scarce. There remains a need for such compounds with the balance of properties suitable for convenient use in a wide array of rodent behavioral studies. We describe here the discovery of a selective mGlub>3b> NAM <b>106b> (VU0650786) suitable for in vivo work. Compound <b>106b> is a member of a series of 5-aryl-6,7-dihydropyrazolo[1,5-a]pyrazine-4(5H)-one compounds originally identified as a mGlub>5b> positive allosteric modulator (PAM) chemotype. Its suitability for use in rodent behavioral models has been established by extensive in vivo PK studies, and the behavioral experiments presented here with compound <b>106b> represent the first examples in which an mGlub>3b> NAM has demonstrated efficacy in models where prior efficacy had previously been noted with nonselective group II antagonists.