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Title: Nowe pochodne chinoksalino-2,3-dionu jako ligandy receptorów kainowych
Abstract:
Kainate receptors are members of the ionotropic glutamate receptors family that mediate rapid excitatory synaptic transmission in the central nervous system. They are present both pre- and postsynaptically and assemble into tetramers from a pool of five subunits (GluK1-5) that differ in activation threshold and functional properties. While selective GluK1 receptor antagonists are relatively well understood and characterised, there is still a lack of pharmacological tools available to study GluK2 and GluK3 subunits. The overall objective of the research presented in the following dissertation was the identification of active and selective ligands of the kainate receptor in the group of quinoxaline-2,3-dione derivatives, with particular emphasis on ligands selective for the GluK3 subunit, the evaluation of the pharmacological properties of the obtained ligands and the performance of computational-aided structure-activity relationship analysis to clarify the structural fragments necessary to achieve high affinity and subunit selectivity. This objective was accomplished within the framework of three projects described in four articles published in international journals, constituting the doctoral dissertation. Project 1 involved the synthesis and pharmacological evaluation of a new radioligand, [3H]-EM17. Within the framework of Project 2, 21 new N1-substituted quinoxaline-2,3-dion ; e derivatives were presented, in which structural modifications were directed at increasing solubility while maintaining full binding capacity to kainate receptors. Derivatives containing sulfamoylphenyl groups in the N1 substituent showed a strong affinity at GluK3 receptors, of which the 7-imidazolyl-6-iodo analogues emerged as entities with most promising in terms of solubility, especially under alkaline conditions. Project 3 presented a series of 25 new 6-arylethyl quinoxaline-2,3-dione derivatives, among which compound N-(6-(imidazo[1,2- b]pyridazin-3-ylethynyl)-2,3-dioxo-3,4-dihydroquinoxalin-1(2H)-yl)benzamide showed an unprecedented 400-fold preference for binding to GluK3 receptors over other homomeric receptors GluK1, GluK2, GluK5 and GluA2.
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Rada Dyscypliny Nauki farmaceutyczne
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Last modified:
Feb 26, 2025
In our library since:
Feb 26, 2025
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http://dl.cm-uj.krakow.pl:8080/publication/5220
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| Edition name | Date |
|---|---|
| ZB-142195 | Feb 26, 2025 |
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