Faculty of Pharmacy and Biotechnology, The German University in Cairo , New Cairo City, 11835 Cairo, Egypt.
Institute of Clinical Neurobiology, University of Würzburg , 97078 Würzburg, Germany.
J Nat Prod. 2016 Dec 23;79(12):2997-3005. doi: 10.1021/acs.jnatprod.6b00479. Epub 2016 Dec 14.
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 [H]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 IC 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.
一系列（E）-11-亚硝异山梨醇肟醚、2-氨基士的宁、（士的宁-2-基）丙酰胺、18-氧化士的宁和 N-丙基士的宁溴化物被合成，并在功能荧光基础和全细胞膜片钳测定以及 [H]士的宁结合研究中在人 α1 和 α1β 甘氨酸受体上进行了药理学评价。2-氨基士的宁和甲基、烯丙基和炔丙基肟醚是该系列中最有效的 α1 和 α1β 拮抗剂，在两个受体上的 IC 值与士的宁相似。对接实验表明，所有类似物在 α3 甘氨酸受体晶体结构的士的宁结合部位的取向相同。对于最有效的肟醚，醚取代基被容纳在亲脂性受体结合口袋中。这些发现确定了肟羟基是通过亚甲基间隔物将两个士的宁药效团连接起来的合适附着点，因此对于设计针对甘氨酸受体的双价配体非常重要。
