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

(11S)-11-Aminostrychnine (1) and N-[(11S)- strychnine-11-yl]propionamide (2) were synthesized and characterized as antagonists of homomericα1 and heteromeric α1β glycine receptorsin a functional fluorescence-based assay and a patch-clampassay and in radioligandbinding studies. The absolute configuration at C-11 of 1 was determined based on vicinal coupling constants and NOESY data. Docking experiments to the orthosteric binding site of the α3 glycine receptorshowed 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 strychnineas a suitable linker group for the future development of dimeric strychnineanalogues targeting glycine receptors. The findings extend the SAR of strychnineat glycine receptors.