Discovery of VU0409106: A negative allosteric modulator of mGlu5 with activity in a mouse model of anxiety.

Felts AS, Rodriguez AL, Morrison RD, Venable DF, Manka JT, Bates BS, Blobaum AL, Byers FW, Daniels JS, Niswender CM, Jones CK, Conn PJ, Lindsley CW, Emmitte KA
Bioorg Med Chem Lett. 2013 23 (21): 5779-85

PMID: 24074843 · PMCID: PMC3846293 · DOI:10.1016/j.bmcl.2013.09.001

Development of SAR in an aryl ether series of mGlu5 NAMs leading to the identification of tool compound VU0409106 is described in this Letter. VU0409106 is a potent and selective negative allosteric modulator of mGlu5 that binds at the known allosteric binding site and demonstrates good CNS exposure following intraperitoneal dosing in mice. VU0409106 also proved efficacious in a mouse marble burying model of anxiety, an assay known to be sensitive to mGlu5 antagonists as well as clinically efficacious anxiolytics.

Copyright © 2013 Elsevier Ltd. All rights reserved.

MeSH Terms (9)

Allosteric Regulation Allosteric Site Animals Anxiety Benzamides Mice Receptor, Metabotropic Glutamate 5 Structure-Activity Relationship Thiazoles

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