Oxime Ethers of (E)-11-Isonitrosostrychnine as Highly Potent Glycine Receptor Antagonists

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• 作者：Amal M. Y. Mohsen ; Yasmine M. Mandour ; Edita Sarukhanyan ; Ulrike Breitinger ; Carmen Villmann ; Maha M. Banoub ; Hans-Georg BreitingerThomas Dandekar ; Ulrike Holzgrabe ; Christoph Sotriffer ; Anders A. JensenDarius P. Zlotos
• 刊名：Journal of Natural Products
• 出版年：2016
• 出版时间：December 23, 2016
• 年：2016
• 卷：79
• 期：12
• 页码：2997-3005
• 全文大小：489K
• ISSN：1520-6025

文摘

A series of (E)-11-isonitrosostrychnine oxime ethers, 2-aminostrychnine, (strychnine-2-yl)propionamide, 18-oxostrychnine, and N-propylstrychnine bromide were synthesized and evaluated pharmacologically at human α1 and α1β glycine receptors in a functional fluorescence-based and a whole-cell patch-clamp assay and in [³H]strychnine binding studies. 2-Aminostrychnine and the methyl, allyl, and propargyl oxime ethers were the most potent α1 and α1β antagonists in the series, displaying IC₅₀ values similar to those of strychnine at the two receptors. Docking experiments to the strychnine binding site of the crystal structure of the α3 glycine receptor indicated the same orientation of the strychnine core for all analogues. For the most potent oxime ethers, the ether substituent was accommodated in a lipophilic receptor binding pocket. The findings identify the oxime hydroxy group as a suitable attachment point for linking two strychnine pharmacophores by a polymethylene spacer and are, therefore, important for the design of bivalent ligands targeting glycine receptors.