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

Abstract

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.

• Authors: Guo Zhu Zheng, Pramila Bhatia, Teodozyj Kolasa, Meena Patel, Odile F El Kouhen, Renjie Chang, Marie E Uchic, Loan Miller, Scott Baker, Sonya G Lehto, Prisca Honore, Jill M Wetter, Kennan C Marsh, Robert B Moreland, Jorge D Brioni, Andrew O Stewart
• Journal: Bioorganic & medicinal chemistry letters (Bioorg Med Chem Lett) Vol. 16 Issue 18 Pg. 4936-40 (Sep 15 2006) ISSN: 0960-894X [Print] England
• PMID: 16809035 (Publication Type: Journal Article)

Chemical References

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

Topics

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