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

(11S)-11-Aminostrychnine (1) and N-[(115)strychnine-11-yl]-propionamide (2) were synthesized and characterized as antagonists of homomeric alpha 1 and heteromeric alpha 1 beta 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 I was determined based on vicinal coupling constants and NOESY data. Docking experiments to the orthosteric binding site of the alpha 3 glycine receptor showed a binding mode of compound 2 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.