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Selective Kainate Receptor (GluK1) Ligands Structurally Based upon 1H-Cyclopentapyrimidin-2,4(1H,3H)-dione: Synthesis, Molecular Modeling, and Pharmacological and Biostructural Characterization
- Source :
- Journal of Medicinal Chemistry. 54:4793-4805
- Publication Year :
- 2011
- Publisher :
- American Chemical Society (ACS), 2011.
-
Abstract
- The physiological function of kainate receptors (GluK1-GluK5) in the central nervous system is not fully understood yet. With the aim of developing potent and selective GluK1 ligands, we have synthesized a series of new thiophene-based GluK1 agonists (6a-c) and antagonists (7a-d). Pharmacological evaluation revealed that they are selective for the GluK1 subunit, with 7b being the most subtype-selective ligand reported to date (GluK1 vs GluK3). The antagonist 7a was cocrystallized with the GluK1 ligand binding domain, and an X-ray crystallographic analysis revealed the largest flexibility in GluK1 ligand binding domain opening upon binding of a ligand seen to date. The results provide new insights into the molecular mechanism of GluK1 receptor ligand binding and pave the way to the development of new tool compounds for studying kainate receptor function.
- Subjects :
- Models, Molecular
Patch-Clamp Techniques
Molecular model
Protein Conformation
Stereochemistry
Protein subunit
Kainate receptor
Thiophenes
Crystallography, X-Ray
Ligands
Cell Line
Structure-Activity Relationship
Xenopus laevis
Receptors, Kainic Acid
Cricetinae
Drug Discovery
Animals
Chemistry
Ligand
Antagonist
Stereoisomerism
Recombinant Proteins
Receptor–ligand kinetics
Rats
Pyrimidines
Membrane protein
Oocytes
Molecular Medicine
Female
Function (biology)
Subjects
Details
- ISSN :
- 15204804 and 00222623
- Volume :
- 54
- Database :
- OpenAIRE
- Journal :
- Journal of Medicinal Chemistry
- Accession number :
- edsair.doi.dedup.....8907ae9e9d48e590bc8ce843a93e0617