Exploring the Orthosteric Binding Site of the 纬-Aminobutyric Acid Type A Receptor Using 4-(Piperidin-4-yl)-1-hydroxypyrazoles 3- or 5-Imidazolyl Substituted: Design, Synthesis, and Pharmacological Eva

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• 作者：Jacob Krall ; Claus H. Jensen ; Troels E. S酶rensen ; Birgitte Nielsen ; Anders A. Jensen ; Tommy Sander ; Thomas Balle ; Bente Fr酶lund
• 刊名：Journal of Medicinal Chemistry
• 出版年：2013
• 出版时间：August 22, 2013
• 年：2013
• 卷：56
• 期：16
• 页码：6536-6540
• 全文大小：302K
• 年卷期：v.56,no.16(August 22, 2013)
• ISSN：1520-4804

文摘

A series of 4-(piperidin-4-yl)-1-hydroxypyrazole (4-PHP) 3- or 5-imidazolyl substituted analogues have been designed, synthesized, and characterized pharmacologically. All analogues showed binding affinities in the low micro- to low nanomolar range at native rat GABA_A receptors and were found to be antagonists at the human 伪₁尾₂纬_2s receptor. The structure鈥揳ctivity relationship of the compound series demonstrates distinct differences in size and architecture of previously discovered cavities in the vicinity of the 4-PHP scaffold in the orthosteric binding site.