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

Sheffler DJ, Wenthur CJ, Bruner JA, Carrington SJ, Vinson PN, Gogi KK, Blobaum AL, Morrison RD, Vamos M, Cosford ND, Stauffer SR, Daniels JS, Niswender CM, Conn PJ, Lindsley CW
Bioorg Med Chem Lett. 2012 22 (12): 3921-5

PMID: 22607673 · PMCID: PMC3365510 · DOI:10.1016/j.bmcl.2012.04.112

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 IC(50) value of 0.66 μM and is inactive against mGlu(5).

Copyright © 2012 Elsevier Ltd. All rights reserved.

MeSH Terms (14)

Allosteric Regulation Cell Line Central Nervous System Drug Discovery Glutamic Acid Humans Microsomes, Liver Molecular Probes Permeability Piperidines Receptor, Metabotropic Glutamate 5 Receptors, Metabotropic Glutamate Sensitivity and Specificity Structure-Activity Relationship

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