Stereoselective synthesis of novel 2′-(S)-CCG-IV analogues as potent NMDA receptor agonists
| Autor: | Rasmus P. Clausen, Tung-Chung Mou, Alex Maolanon, Kasper B. Hansen, Feng Yi, David Kawiecki, Jed T. Syrenne, Athanasios Papangelis |
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| Jazyk: | angličtina |
| Rok vydání: | 2021 |
| Předmět: |
Models
Molecular Agonist congenital hereditary and neonatal diseases and abnormalities Stereochemistry medicine.drug_class Crystallography X-Ray Receptors N-Methyl-D-Aspartate Article law.invention Structure-Activity Relationship Synthesis law Drug Discovery medicine Humans Receptor (carboxycyclopropyl)glycine X-ray crystallography Pharmacology Dose-Response Relationship Drug Molecular Structure Chemistry Organic Chemistry Glutamate receptor Stereoisomerism Glutamate binding General Medicine Amino Acids Dicarboxylic NMDA Recombinant DNA NMDA receptor Stereoselectivity Binding domain |
| Zdroj: | Maolanon, A, Papangelis, A, Kawiecki, D, Mou, T C, Syrenne, J T, Yi, F, Hansen, K B & Clausen, R P 2021, ' Stereoselective synthesis of novel 2′-(S)-CCG-IV analogues as potent NMDA receptor agonists ', European Journal of Medicinal Chemistry, vol. 212, 113099 . https://doi.org/10.1016/j.ejmech.2020.113099 Eur J Med Chem |
| DOI: | 10.1016/j.ejmech.2020.113099 |
| Popis: | We developed a versatile stereoselective route for the synthesis of new 2′-(S)-CCG-IV analogues. The route allows for late stage diversification and thereby provides access to a great variety of conformationally restricted cyclopropyl glutamate analogues. A selection of the 2′-(S)-CCG-IV analogues were evaluated using two-electrode voltage-clamp electrophysiology at recombinant GluN1/GluN2A-D receptors, demonstrating that agonists can be developed with GluN2 subunit-dependent potency and agonist efficacy. We also describe a crystal structure of the GluN2A agonist binding domain in complex with 2′-butyl-(S)-CCG-IV that determines the position of 2′-substituents in (S)-CCG-IV agonists in the glutamate binding site and provides further insight to the structural determinants of their agonist efficacy. The stereoselective synthesis described here enables versatile and straight-forward modifications to diverse analogues of interest for the development of potent subtype-specific NMDA receptor agonists and other applications. |
| Databáze: | OpenAIRE |
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