11-Aminostrychnine and N-(Strychnine-11-yl)propionamide: Synthesis, Configuration, and Pharmacological Evaluation at Glycine Receptors

Journal of Natural Products
2019.0

Abstract

(11<i>S</i>)-11-Aminostrychnine (<b>1</b>) and <i>N</i>-[(11<i>S</i>)-strychnine-11-yl]propionamide (<b>2</b>) were synthesized and characterized as antagonists of homomeric α1 and heteromeric α1β glycine receptors in a functional fluorescence-based assay and a patch-clamp assay and in radioligand binding studies. The absolute configuration at C-11 of <b>1</b> was determined based on vicinal coupling constants and NOESY data. Docking experiments to the orthosteric binding site of the α3 glycine receptor showed a binding mode of compound <b>2</b> analogous to that of strychnine, explaining its high antagonistic potency. The findings identify the C-11 amide function of strychnine as a suitable linker group for the future development of dimeric strychnine analogues targeting glycine receptors. The findings extend the SAR of strychnine at glycine receptors.

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