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 Allop

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• 作者：Mingxing Qian ; Kathiresan Krishnan ; Eva Kudova ; Ping Li ; Brad D. Manion ; Amanda Taylor ; George Elias ; Gustav Akk ; Alex S. Evers ; Charles F. Zorumski ; Steven Mennerick ; Douglas F. Covey
• 刊名：Journal of Medicinal Chemistry
• 出版年：2014
• 出版时间：January 9, 2014
• 年：2014
• 卷：57
• 期：1
• 页码：171-190
• 全文大小：678K
• ISSN：1520-4804

文摘

A model of the alignment of neurosteroids and ent-neurosteroids at the same binding site on 纬-aminobutyric acid type A (GABA_A) 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 4伪-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 GABA_A receptor function.