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

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

  • Bioorg Med Chem Lett. 2012 Oct 15;22(20):6481-5. doi: 10.1016/j.bmcl.2012.08.043.
Jason T Manka 1,  Paige N Vinson,  Karen J Gregory,  Ya Zhou,  Richard Williams,  Kiran Gogi,  Emily Days,  Satya Jadhav,  Elizabeth J Herman,  Hilde Lavreysen,  Claire Mackie,  José M Bartolomé,  Gregor J Macdonald,  Thomas Steckler,  J Scott Daniels,  C David Weaver,  Colleen M Niswender,  Carrie K Jones,  P Jeffrey Conn,  Craig W Lindsley,  Shaun R Stauffer
Affiliations

Affiliation

  • 1 Department of Pharmacology, Vanderbilt University Medical Center, Nashville, TN 37232, USA.
PMID: 22981332 DOI: 10.1016/j.bmcl.2012.08.043
Abstract

We report the optimization of a series of non-MPEP site metabotropic glutamate receptor 5 (mGlu(5)) 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.

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