Enaminone Amides as Novel Orally Active GABAA Receptor Modulators

详细信息    查看全文

• 作者：Derk J. Hogenkamp ; Timothy B. C. Johnstone ; Jin-Cheng Huang ; Wen-Yen Li ; Minhtam Tran ; Edward R. Whittemore ; Rudy E. Bagnera ; Kelvin W. Gee
• 刊名：Journal of Medicinal Chemistry
• 出版年：2007
• 出版时间：July 12, 2007
• 年：2007
• 卷：50
• 期：14
• 页码：3369 - 3379
• 全文大小：177K
• 年卷期：v.50,no.14(July 12, 2007)
• ISSN：1520-4804

文摘

A series of enaminone esters and amides have been developed as potent allosteric modulators of-aminobutyric acid_A (GABA_A) receptors. The compounds bind to a novel modulatory site that is independentof the benzodiazepine (BZ), isosteric GABA, and neuroactive steroid binding sites. Structure-activityrelationship (SAR) studies resulted in the synthesis of the c-Bu amide 16h with an in vitro potency of 7 nMbased on inhibition of [³⁵S]TBPS binding. The activity of the enaminones as positive allosteric modulatorswas confirmed with electrophysiological measurements in oocytes expressing _122L GABA_A receptors.The i-Pr, s-Bu, c-Pr, and c-Bu amides (16e-h) were orally active in mice with profound central nervoussystem depressant effects. The i-Pr amide 16e was an orally active anxiolytic in the mouse light-darkparadigm.