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

Manka JT, Vinson PN, Gregory KJ, Zhou Y, Williams R, Gogi K, Days E, Jadhav S, Herman EJ, Lavreysen H, Mackie C, Bartolomé JM, Macdonald GJ, Steckler T, Daniels JS, Weaver CD, Niswender CM, Jones CK, Conn PJ, Lindsley CW, Stauffer SR
Bioorg Med Chem Lett. 2012 22 (20): 6481-5

PMID: 22981332 · PMCID: PMC3755010 · DOI:10.1016/j.bmcl.2012.08.043

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.

Copyright © 2012 Elsevier Ltd. All rights reserved.

MeSH Terms (12)

Allosteric Regulation Allosteric Site Animals Antipsychotic Agents Ethers Humans Niacinamide Psychotic Disorders Rats Receptor, Metabotropic Glutamate 5 Receptors, Metabotropic Glutamate Structure-Activity Relationship

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