神经甾体类似物。18. γ-氨基丁酸 A 型受体激动剂的结构-活性研究及与阿尔法羟孕酮和孕烷醇酮活性的比较。

Neurosteroid analogues. 18. Structure-activity studies of ent-steroid potentiators of γ-aminobutyric acid type A receptors and comparison of their activities with those of alphaxalone and allopregnanolone.

机构信息

Departments of Developmental Biology, ‡Anesthesiology, §Psychiatry, and ⊥Anatomy and Neurobiology, Washington University in St. Louis School of Medicine , St. Louis, Missouri, 63110, United States.

出版信息

J Med Chem. 2014 Jan 9;57(1):171-90. doi: 10.1021/jm401577c. Epub 2013 Dec 24.

A model of the alignment of neurosteroids and ent-neurosteroids at the same binding site on γ-aminobutyric acid type A (GABAA) receptors was evaluated for its ability to identify the structural features in ent-neurosteroids that enhance their activity as positive allosteric modulators of this receptor. Structural features that were identified included: (1) a ketone group at position C-16, (2) an axial 4α-OMe group, and (3) a C-18 methyl group. Two ent-steroids were identified that were more potent than the anesthetic steroid alphaxalone in their threshold for and duration of loss of the righting reflex in mice. In tadpoles, loss of righting reflex for these two ent-steroids occurs with EC50 values similar to those found for allopregnanolone. The results indicate that ent-steroids have considerable potential to be developed as anesthetic agents and as drugs to treat brain disorders that are ameliorated by positive allosteric modulators of GABAA receptor function.

评估了神经甾体和内源性神经甾体在 GABA 型 A 受体 (GABAA) 同一结合位点上的排列模型，以确定内源性神经甾体中增强其作为该受体的正变构调节剂活性的结构特征。确定的结构特征包括：（1）C-16 位的酮基，（2）轴向 4α-OMe 基团，和（3）C-18 甲基。鉴定出两种内源性甾体，它们在诱发小鼠翻正反射丧失的阈值和持续时间方面比麻醉甾体 alphaxalone 更有效。在蝌蚪中，这两种内源性甾体引起翻正反射丧失的 EC50 值与发现的 allopregnanolone 相似。结果表明，内源性甾体具有很大的潜力，可以开发为麻醉剂，并开发用于治疗脑功能障碍的药物，这些药物通过 GABA 受体功能的正变构调节剂得到改善。