Department of Chemistry, AstraZeneca Pharmaceuticals, Wilmington, DE 19850, USA.
Bioorg Med Chem. 2011 May 1;19(9):2927-38. doi: 10.1016/j.bmc.2011.03.035. Epub 2011 Mar 29.
Positive modulators at the benzodiazepine site of α2- and α3-containing GABA(A) receptors are believed to be anxiolytic. Through oocyte voltage clamp studies, we have discovered two series of compounds that are positive modulators at α2-/α3-containing GABA(A) receptors and that show no functional activity at α1-containing GABA(A) receptors. We report studies to improve this functional selectivity and ultimately deliver clinical candidates. The functional SAR of cinnolines and quinolines that are positive allosteric modulators of the α2- and α3-containing GABA(A) receptors, while simultaneously neutral antagonists at α1-containing GABA(A) receptors, is described. Such functionally selective modulators of GABA(A) receptors are expected to be useful in the treatment of anxiety and other psychiatric illnesses.
苯二氮䓬 site 的正变构调节剂在 α2- 和 α3 包含的 GABA(A) 受体中被认为是抗焦虑的。通过卵母细胞电压钳研究，我们发现了两个系列的化合物，它们是 α2-/α3 包含的 GABA(A) 受体的正变构调节剂，并且在 α1 包含的 GABA(A) 受体中没有功能活性。我们报告了改善这种功能选择性并最终提供临床候选药物的研究。描述了作为 α2- 和 α3 包含的 GABA(A) 受体的正变构调节剂，同时作为 α1 包含的 GABA(A) 受体的中性拮抗剂的肉桂素和喹啉的功能 SAR。这种 GABA(A) 受体的功能选择性调节剂有望在焦虑症和其他精神疾病的治疗中有用。
