مؤتمر
Design of potentiators targeting the allosteric pocket of the kainate subtype glutamate receptors
| العنوان: | Design of potentiators targeting the allosteric pocket of the kainate subtype glutamate receptors |
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| المؤلفون: | Colson, Thomas, Valembois, S., Leroy, Charline, Bay, Y., Pickering, D.S., Kristensen, A.S., Pirotte, Bernard, Kastrup, J.S., Francotte, Pierre |
| المساهمون: | CIRM - Centre Interdisciplinaire de Recherche sur le Médicament - ULiège, BE |
| المصدر: | 10th EFMC Young Medicinal Chemist Symposium (EFMC-YMCS), Zagreb, Croatia [HR], September 7 and 8, 2023 |
| سنة النشر: | 2023 |
| مصطلحات موضوعية: | kainate, receptor, PAM, Allosteric Modulator, Positive Allosteric Modulator, Glutamate, benzothiadiazines dioxydes, BPAM344, BPAM121, BPAM521, IDRA21, AMPA, GluK1, Ligand, GluK2, GluK3, Drug, Alzheimer, Human health sciences, Pharmacy, pharmacology & toxicology, Sciences de la santé humaine, Pharmacie, pharmacologie & toxicologie |
| الوصف: | editorial reviewed Based on the major role played by glutamate in our brain, the glutamatergic receptors always constitute interesting targets to develop therapeutics. Amongst all the pharmacological classes that have been investigated so far stand the AMPA receptor (AMPAR) positive allosteric modulators (AMPARpams).Over the two last decades, our laboratory has been involved in the design of such compounds, namely preparing more than five hundred original 1,2,4-benzothiadiazine 1,1-dioxides and isosteres related to IDRA-21 acting as AMPARpams.Amongst the lead compounds, some ligands such as BPAM344 were co-crystallized with the ligand-binding domain (LBD) of the GluK1 subunit of kainate receptors (KARs). BPAM344 was shown to interact at the allosteric site of the GluK1-LBD dimer interface supporting the view that this drug behaves as a KARpam. This breakthrough was confirmed after voltage-clamp experiments with homomeric GluK1b, GluK2a or GluK3 KARs expressed in HEK293 cells. BPAM344 was found to potentiate KARs, albeit at higher concentrations than required for potentiation of AMPA receptors [1].Due to the structural analogy between AMPA and KA receptors and considering the recent knowledge of existing differences in residues at the level of their dimer interface after alignment of both receptors, a rational drug design leading to specific ligands for the KARs was explored.Taking into account these data, the present work focused on the insertion of hydrocarbon chain bearing specific polar moieties on the nitrogen atom at the 4-position of BTDs with the aim to interact with specific amino-acid residues of the KAR allosteric site.[1] Larsen et al., Molecular Pharmacology (2017), 91, 576-585; doi :10.1124/mol.116.107599 |
| نوع الوثيقة: | conference poster not in proceedings http://purl.org/coar/resource_type/c_18co conferencePoster editorial reviewed |
| اللغة: | English |
| URL الوصول: | https://orbi.uliege.be/handle/2268/307922 |
| رقم الأكسشن: | edsorb.307922 |
| قاعدة البيانات: | ORBi |
| الوصف غير متاح. |