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

作者：Engers Julie L; Rodriguez Alice L; Konkol Leah C; Morrison Ryan D; Thompson Analisa D; Byers Frank W; Blobaum Anna L; Chang Sichen; Venable Daryl F; Loch Matthew T; Niswender Colleen M; Daniels J Scott; Jones Carrie K; Conn P Jeffrey; Lindsley Craig W; Emmitte Kyle A^*

来源：Journal of Medicinal Chemistry, 2015, 58(18): 7485-7500.

DOI：10.1021/acs.jmedchem.5b01005

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 (mGlu(2) and mGlu(3)) 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 mGlu(3) NAM 106 (VU0650786) suitable for in vivo work. Compound 106 is a member of a series of 5-aryl-6,7-dihydropyrazolo[1,5-a]pyrazine-4(5H)-one compounds originally identified as a mGlu(5) 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 106 represent the first examples in which an mGlu(3) NAM has demonstrated efficacy in models where prior efficacy had previously been noted with nonselective group II antagonists.

• 出版日期2015-9-24