Development of a novel, CNS-penetrant, metabotropic glutamate receptor 3 (mGlu(3)) NAM probe (ML289) derived from a closely related mGlu(5) PAM

Sheffler Douglas J; Wenthur Cody J; Bruner Joshua A; Carrington Sheridan J S; Vinson Paige N; Gogi Kiran K; Blobaum Anna L; Morrison Ryan D; Vamos Mitchell; Cosford Nicholas D P; Stauffer Shaun R; Daniels J Scott; Niswender Colleen M; Conn P Jeffrey; Lindsley Craig W<sup>*</sup>

doi:10.1016/j.bmcl.2012.04.112

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Development of a novel, CNS-penetrant, metabotropic glutamate receptor 3 (mGlu(3)) NAM probe (ML289) derived from a closely related mGlu(5) PAM

作者：Sheffler Douglas J; Wenthur Cody J; Bruner Joshua A; Carrington Sheridan J S; Vinson Paige N; Gogi Kiran K; Blobaum Anna L; Morrison Ryan D; Vamos Mitchell; Cosford Nicholas D P; Stauffer Shaun R; Daniels J Scott; Niswender Colleen M; Conn P Jeffrey; Lindsley Craig W^*

来源：Bioorganic & Medicinal Chemistry Letters, 2012, 22(12): 3921-3925.

DOI：10.1016/j.bmcl.2012.04.112

摘要

Herein we report the discovery and SAR of a novel metabotropic glutamate receptor 3 (mGlu(3)) NAM probe (ML289) with 15-fold selectivity versus mGlu(2). The mGlu(3) NAM was discovered via a 'molecular switch' from a closely related, potent mGlu(5) positive allosteric modulator (PAM), VU0092273. This NAM (VU0463597, ML289) displays an IC50 value of 0.66 mu M and is inactive against mGlu(5).