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

2006; Elsevier BV; Volume: 16; Issue: 18 Linguagem: Inglês

10.1016/j.bmcl.2006.06.053

1464-3405

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 Honoré, Jill M. Wetter, Kennan C. Marsh, Robert B. Moreland, Jorge D. Brioni, Andrew O. Stewart,

Pain Mechanisms and Treatments

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.