Development of a novel, CNS-penetrant, metabotropic glutamate receptor 3 (mGlu3) NAM probe (ML289) derived from a closely related mGlu5 PAM

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS

卷:22

Article

Sheffler, Douglas J.^1,2,3  Wenthur, Cody J.^1,2  Bruner, Joshua A.²  Carrington, Sheridan J. S.^1,2  Vinson, Paige N.^1,2  Gogi, Kiran K.^1,2  Blobaum, Anna L.^1,2,3  Morrison, Ryan D.^1,2,3  Vamos, Mitchell^5,6  Cosford, Nicholas D. P.^5,6  Stauffer, Shaun R.^1,2,4  Daniels, J. Scott^1,2,3  Niswender, Colleen M.^1,2  Conn, P. Jeffrey^1,2,3  Lindsley, Craig W.^1,2,3,4 

[1] Vanderbilt Univ, Med Ctr, Dept Pharmacol, Nashville, TN 37232 USA

[2] Vanderbilt Univ, Med Ctr, Vanderbilt Ctr Neurosci Drug Discovery, Nashville, TN 37232 USA

[3] Vanderbilt Specialized Chem Ctr Probe Dev MLPCN, Nashville, TN 37232 USA

[4] Vanderbilt Univ, Dept Chem, Nashville, TN 37232 USA

[5] Sanford Burnham Med Res Inst, Apoptosis & Cell Death Res Program, La Jolla, CA 92037 USA

[6] Sanford Burnham Med Res Inst, Conrad Prebys Ctr Chem Genom, La Jolla, CA 92037 USA

关键词: Metabotropic glutamate receptor 3;    mGlu(3);    Molecular switch;    NAM;   

DOI  :  10.1016/j.bmcl.2012.04.112

来源: Elsevier

【 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). (C) 2012 Elsevier Ltd. All rights reserved.

【 授权许可】

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