Zheng Guo Zhu, Bhatia Pramila, Kolasa Teodozyj, Patel Meena, El Kouhen Odile F, Chang Renjie, Uchic Marie E, Miller Loan, Baker Scott, Lehto Sonya G, Honore Prisca, Wetter Jill M, Marsh Kennan C, Moreland Robert B, Brioni Jorge D, Stewart Andrew O
Neuroscience Research, Abbott Laboratories, 100 Abbott Park Road, Abbott Park, IL 60064-6115, USA.
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.
我们发现了一类新型、强效且具有选择性的三氮杂芴酮类代谢型谷氨酸受体1（mGluR1）拮抗剂，它们在多种大鼠疼痛模型中均有效。这些三氮杂芴酮类似物的药代动力学和药效学特征表明，这些mGluR1拮抗剂的脑/血浆比值对于在神经性疼痛模型中取得疗效很重要。这种相关性可用于指导我们进行体内构效关系（SAR）修饰。例如，化合物4a的脑/血浆比值为0.34，在神经性疼痛模型中仅表现出中等疗效。另一方面，脑/血浆比值为2.70的拮抗剂4b在神经性疼痛模型中具有完全疗效。
