Optimization of an ether series of mGlu5 positive allosteric modulators: molecular determinants of MPEP-site interaction crossover

Jason T Manka, Paige N Vinson, Karen Joan Gregory, Ya Zhou, Richard E A Williams, Kiran Gogi, Emily Days, Satya Jadhav, Elizabeth J Herman, Hilde Lavreysen, Claire Mackie, Jose Bartolome, Gregor J Macdonald, Thomas Steckler, John Scott Daniels, C David Weaver, Colleen M Niswender, Carrie K Jones, Peter Jeffrey Conn, Craig W LindsleyShaun R Stauffer

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Abstract

We report the optimization of a series of non-MPEP site metabotropic glutamate receptor 5 (mGlu5) positive allosteric modulators (PAMs) based on a simple acyclic ether series. Modifications led to a gain of MPEP site interaction through incorporation of a chiral amide in conjunction with a nicotinamide core. A highly potent PAM, 8v (VU0404251), was shown to be efficacious in a rodent model of psychosis. These studies suggest that potent PAMs within topologically similar chemotypes can be developed to preferentially interact or not interact with the MPEP allosteric binding site.
Original languageEnglish
Pages (from-to)6481 - 6485
Number of pages5
JournalBioorganic and Medicinal Chemistry Letters
Volume22
Issue number20
DOIs
Publication statusPublished - 2012

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