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. Epub 2012 Aug 24.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Allosteric Regulation / drug effects*
  • Allosteric Site / drug effects
  • Animals
  • Antipsychotic Agents / chemistry*
  • Antipsychotic Agents / pharmacology*
  • Antipsychotic Agents / therapeutic use
  • Ethers / chemistry
  • Ethers / pharmacology
  • Ethers / therapeutic use
  • Humans
  • Niacinamide / chemistry*
  • Niacinamide / pharmacology*
  • Niacinamide / therapeutic use
  • Psychotic Disorders / drug therapy
  • Rats
  • Receptor, Metabotropic Glutamate 5
  • Receptors, Metabotropic Glutamate / chemistry
  • Receptors, Metabotropic Glutamate / metabolism*
  • Structure-Activity Relationship

Substances

  • Antipsychotic Agents
  • Ethers
  • Receptor, Metabotropic Glutamate 5
  • Receptors, Metabotropic Glutamate
  • Niacinamide