Challenges in the development of mGluR5 positive allosteric modulators: the discovery of CPPHA

Bioorg Med Chem Lett. 2007 Mar 1;17(5):1386-91. doi: 10.1016/j.bmcl.2006.11.081. Epub 2006 Dec 3.


This Letter describes, for the first time, the synthesis and SAR, developed through an iterative analog library approach, that led to the discovery of the positive allosteric modulator (PAM) of the metabotropic glutamate receptor mGluR5 CPPHA. Binding to a unique allosteric binding site distinct from other mGluR5 PAMs, CPPHA has been the focus of numerous pharmacology studies by several laboratories.

MeSH terms

  • Allosteric Regulation*
  • Allosteric Site
  • Animals
  • Benzamides / chemistry*
  • Benzamides / pharmacology*
  • Humans
  • Phthalimides / chemistry*
  • Phthalimides / pharmacology*
  • Rats
  • Receptor, Metabotropic Glutamate 5
  • Receptors, Metabotropic Glutamate / drug effects*
  • Structure-Activity Relationship


  • Benzamides
  • GRM5 protein, human
  • Grm5 protein, rat
  • N-(4-chloro-2-((1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)methyl)phenyl)-2-hydroxybenzamide
  • Phthalimides
  • Receptor, Metabotropic Glutamate 5
  • Receptors, Metabotropic Glutamate