Department of Biomedical and Pharmaceutical Sciences, University of Montana, Missoula, MT 59812, United States.
Skaggs School of Pharmacy and Pharmaceutical Sciences, Anschutz Medical Campus, University of Colorado Denver, Aurora, CO 80045, United States.
Bioorg Med Chem. 2018 Sep 15;26(17):4797-4803. doi: 10.1016/j.bmc.2018.08.012. Epub 2018 Aug 10.
Isoxazolo[3,4-d] pyridazinones ([3,4-d]s) are selective positive modulators of the metabotropic glutamate receptors (mGluRs) subtypes 2 and 4, with no functional cross reactivity at mGluR, mGLuR or mGluR. Modest binding for two of the [3,4-d]s is observed at the allosteric fenobam mGluR site, but not sufficient to translate into a functional effect. The structure activity relationship (SAR) for mGluR and mGluR are distinct: the compounds which select for mGluR all contain fluorine on the N-6 aryl group. Furthermore, the [3,4-d]s in this study showed no significant binding at inhibitory GABA nor excitatory NMDA receptors, and previously we had disclosed that they lack significant activity at the System Xc-Antiporter. A homology model based on Conn's mGluR crystal structure was examined, and suggested explanations for a preference for allosteric over orthosteric binding, subtype selectivity, and suggested avenues for optimization of efficacy as a reasonable working hypothesis.
异恶唑并[3,4-d]哒嗪酮类化合物 ([3,4-d]s) 是代谢型谷氨酸受体 (mGluRs) 亚型 2 和 4 的选择性正变构调节剂，对 mGluR、mGLuR 或 mGluR 没有功能性交叉反应活性。在变构苯并戊胺 mGluR 结合位点观察到两个 [3,4-d]s 的适度结合，但不足以转化为功能效应。mGluR 和 mGluR 的构效关系 (SAR) 不同：选择 mGluR 的化合物在 N-6 芳基上都含有氟。此外，本研究中的 [3,4-d]s 在抑制性 GABA 或兴奋性 NMDA 受体上没有明显结合，而之前我们已经披露它们在 System Xc-Antiporter 上没有明显活性。检查了基于 Conn 的 mGluR 晶体结构的同源模型，并提出了对变构结合而非正构结合、亚型选择性的偏好的解释，并提出了优化功效的途径，作为一个合理的工作假设。
