Correlation between brain/plasma ratios and efficacy in neuropathic pain models of selective metabotropic glutamate receptor 1 antagonists
| Autor: | Scott J. Baker, Loan N. Miller, Meena V. Patel, Marie E. Uchic, Kennan C. Marsh, Prisca Honore, Renjie Chang, Odile F. El Kouhen, Guo Zhu Zheng, Pramila Bhatia, Jorge D. Brioni, Robert B. Moreland, Sonya G. Lehto, Jill M. Wetter, Andrew O. Stewart, Teodozyj Kolasa |
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| Rok vydání: | 2006 |
| Předmět: |
Stereochemistry
Clinical Biochemistry Analgesic Pain Pharmaceutical Science Pharmacology Receptors Metabotropic Glutamate Blood–brain barrier Biochemistry Cell Line Structure-Activity Relationship In vivo Drug Discovery medicine Animals Humans Molecular Biology Neurons Aza Compounds Molecular Structure Chemistry Organic Chemistry Glutamate receptor Antagonist Brain Rats medicine.anatomical_structure Metabotropic receptor Models Animal Neuropathic pain Molecular Medicine Metabotropic glutamate receptor 1 |
| Zdroj: | Bioorganic & Medicinal Chemistry Letters. 16:4936-4940 |
| ISSN: | 0960-894X |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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