Correlation between brain/plasma ratios and efficacy in neuropathic pain models of selective metabotropic glutamate receptor 1 antagonists

Bioorg Med Chem Lett. 2006 Sep 15;16(18):4936-40. doi: 10.1016/j.bmcl.2006.06.053. Epub 2006 Jun 30.


We have discovered a novel, potent, and selective triazafluorenone series of metabotropic glutamate receptor 1 (mGluR1) antagonists with efficacy in various rat pain models. Pharmacokinetic and pharmacodynamic profiles of these triazafluorenone analogs revealed that brain/plasma ratios of these mGluR1 antagonists were important to achieve efficacy in neuropathic pain models. This correlation could be used to guide our in vivo SAR (structure-activity relationship) modification. For example, compound 4a has a brain/plasma ratio of 0.34, demonstrating only moderate efficacy in neuropathic pain models. On the other hand, antagonist 4b with a brain/plasma ratio of 2.70 was fully efficacious in neuropathic pain models.

MeSH terms

  • Animals
  • Aza Compounds / blood
  • Aza Compounds / chemical synthesis*
  • Aza Compounds / chemistry
  • Aza Compounds / pharmacology*
  • Brain / drug effects*
  • Brain / metabolism
  • Cell Line
  • Humans
  • Models, Animal
  • Molecular Structure
  • Neurons / drug effects*
  • Neurons / metabolism*
  • Pain / drug therapy*
  • Pain / metabolism
  • Rats
  • Receptors, Metabotropic Glutamate / antagonists & inhibitors*
  • Receptors, Metabotropic Glutamate / metabolism
  • Structure-Activity Relationship


  • Aza Compounds
  • Receptors, Metabotropic Glutamate
  • metabotropic glutamate receptor type 1