Department of Biomedical and Pharmaceutical Sciences, University of Montana, 32 Campus Drive, Missoula, MT 59812, USA.
Skaggs School of Pharmacy and Pharmaceutical Sciences, Anschutz Medical Campus, University of Colorado Denver, Aurora, CO 80045, USA.
Molecules. 2023 Sep 25;28(19):6800. doi: 10.3390/molecules28196800.
Isoxazolo[3,4-] pyridazinones ([3,4-]s) were previously shown to have selective positive modulation at the metabotropic glutamate receptor (mGluR) Subtypes 2 and 4, with no functional cross-reactivity at mGluR, mGluR, or mGluR. Additional analogs were prepared to access more of the allosteric pocket and achieve higher binding affinity, as suggested by homology modeling. Two different sets of analogs were generated. One uses the fully formed [3,4-] with an N6-aryl with and without halogens. These underwent successful selective lateral metalation and electrophilic quenching (LM&EQ) at the C3 of the isoxazole. In a second set of analogs, a phenyl group was introduced at the C4 position of the [3,4-] ring via a condensation of 4-phenylacetyl-3-ethoxcarbonyl-5-methyl isoxazole with the corresponding hydrazine to generate the 3,4-s and to .
异噁唑并[3,4-]哒嗪酮([3,4-]s)先前被证明对代谢型谷氨酸受体(mGluR)亚型 2 和 4 具有选择性正变构调节作用，而对 mGluR、mGluR 或 mGluR 没有功能交叉反应性。根据同源建模的建议，制备了其他类似物以进入更多的变构口袋并实现更高的结合亲和力。生成了两组不同的类似物。一组使用完全形成的[3,4-]，其中 N6-芳基带有和不带有卤素。这些在异噁唑的 C3 上成功地进行了选择性的侧向金属化和亲电淬灭（LM&EQ）。在第二组类似物中，通过将 4-苯基乙酰基-3-乙氧羰基-5-甲基异噁唑与相应的肼缩合，在[3,4-]环的 C4 位置引入一个苯基，生成 3,4-s 和 。
