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Optimization of an ether series of mGlu5 positive allosteric modulators: molecular determinants of MPEP-site
Jason T Manka1, Paige N Vinson, Karen J Gregory
1Department of Pharmacology, Vanderbilt University Medical Center, Nashville, TN 37232, USA.
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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