11-Aminostrychnine and N-(Strychnine-11-yl)propionamide: Synthesis, Configuration, and Pharmacological Evaluation at Glycine Receptors
| Autor: | Hans-Georg Breitinger, Darius P. Zlotos, Carmen Villmann, Christoph A. Sotriffer, Anders A. Jensen, Amal M. Y. Mohsen, Ulrike Holzgrabe, Yasmine M. Mandour, Mohamed Akmal Marzouk, Ulrike Breitinger |
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| Rok vydání: | 2019 |
| Předmět: |
Pharmacology
010405 organic chemistry Stereochemistry Organic Chemistry Absolute configuration Pharmaceutical Science Strychnine 01 natural sciences 0104 chemical sciences Analytical Chemistry 010404 medicinal & biomolecular chemistry chemistry.chemical_compound Complementary and alternative medicine chemistry Docking (molecular) Drug Discovery Molecular Medicine Homomeric Structure–activity relationship Binding site Receptor Glycine receptor |
| Zdroj: | Journal of Natural Products. 82:2332-2336 |
| ISSN: | 1520-6025 0163-3864 |
| DOI: | 10.1021/acs.jnatprod.9b00180 |
| Popis: | (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. |
| Databáze: | OpenAIRE |
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