Author/Authors :
Guo Zhu Zheng، نويسنده , , Pramila Bhatia، نويسنده , , Teodozyj Kolasa، نويسنده , , Meena Patel، نويسنده , , Odile F. El Kouhen، نويسنده , , Renjie Chang، نويسنده , , Marie E. Uchic، نويسنده , , Loan Miller، نويسنده , , Scott Baker، نويسنده , , Sonya G. Lehto، نويسنده , , Prisca Honore، نويسنده , , Jill M. Wetter، نويسنده , , Kennan C. Marsh، نويسنده , , Robert B. Moreland، نويسنده , , Jorge D. Brioni، نويسنده , , Andrew O. Stewart، نويسنده ,
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.
Keywords :
glutamate , Metabotropic , Antagonist , mGluR1 , Neuropathic pain , receptor
