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

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 receptorsin a functional fluorescence-based and a whole-cell patch-clampassay and in [3H] strychninebinding studies. 2-Aminostrychnine and the methyl, allyl, and propargyl oxime etherswere the most potent α1 and α1β antagonists in the series, displaying IC50 values similar to those of strychnineat the two receptors. Docking experiments to the strychninebinding site of the crystal structure of the α3 glycine receptorindicated the same orientation of the strychninecore for all analogues. For the most potent oxime ethers, the ethersubstituent was accommodated in a lipophilic receptor binding pocket. The findings identify the oxime hydroxy groupas a suitable attachment point for linking two strychnine pharmacophoresby a polymethylene spacer and are, therefore, important for...