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

• Published in: Journal of natural products (Washington, D.C.) Vol. 82; no. 8; pp. 2332 - 2336
• Main Authors: Zlotos, Darius P, Mohsen, Amal M. Y, Mandour, Yasmine M, Marzouk, Mohamed A, Breitinger, Ulrike, Villmann, Carmen, Breitinger, Hans-Georg, Sotriffer, Christoph, Jensen, Anders A, Holzgrabe, Ulrike
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society and American Society of Pharmacognosy 23.08.2019; Amer Chemical Soc
• Subjects: Chemistry, Medicinal; Life Sciences & Biomedicine; Pharmacology & Pharmacy; Plant Sciences; Science & Technology; STRYCHNINE; ANTAGONIST; MECHANISM; BRUCINE; ANALOGS; FUNCTIONAL-CHARACTERIZATION; GENETIC ALGORITHM
• ISSN: 0163-3864; 1520-6025
• DOI: 10.1021/acs.jnatprod.9b00180

(11S)-11-Aminostrychnine (1) and N-[(11S)-strychnine-11-yl]­propionamide (2) 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 1 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 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.