MPX-004 and MPX-007: New Pharmacological Tools to Study the Physiology of NMDA Receptors Containing the GluN2A Subunit
| Autor: | Frank S. Menniti, Esther Steidl, Earl Gordon, Michela Fagiolini, Bruno Buisson, Caterina Virginio, Kathy Paschetto, Volkmann Robert A, Melanie Gleyzes, Christopher Fanger, David E. Anderson, Susanna B. Mierau, Venkata Ramana Sirivolu |
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| Jazyk: | angličtina |
| Rok vydání: | 2016 |
| Předmět: |
0301 basic medicine
Xenopus Physiology lcsh:Medicine Pharmacology Biochemistry 0302 clinical medicine Animal Cells Electrochemistry Amino Acids Receptor lcsh:Science Neurons Multidisciplinary biology Organic Compounds Glutamate receptor Neurochemistry Animal Models Neurotransmitters Chemistry Physical Sciences Xenopus Oocytes Vertebrates Excitatory postsynaptic potential NMDA receptor Frogs Cell lines Cellular Types Glutamate Biological cultures Receptor Physiology Research Article Cell Physiology Materials Science Material Properties Glycine Research and Analysis Methods Amphibians 03 medical and health sciences Model Organisms Animals Electrode Potentials HEK 293 cells Organic Chemistry lcsh:R Chemical Compounds Organisms Biology and Life Sciences Proteins Glutamic acid Cell Biology biology.organism_classification 030104 developmental biology Aliphatic Amino Acids Solubility biology.protein GRIN2A lcsh:Q 030217 neurology & neurosurgery Neuroscience |
| Zdroj: | PLoS ONE, Vol 11, Iss 2, p e0148129 (2016) PLoS ONE |
| ISSN: | 1932-6203 |
| Popis: | GluN2A is the most abundant of the GluN2 NMDA receptor subunits in the mammalian CNS. Physiological and genetic evidence implicate GluN2A-containing receptors in susceptibility to autism, schizophrenia, childhood epilepsy and neurodevelopmental disorders such as Rett Syndrome. However, GluN2A-selective pharmacological probes to explore the therapeutic potential of targeting these receptors have been lacking. Here we disclose a novel series of pyrazine-containing GluN2A antagonists exemplified by MPX-004 (5-(((3-chloro-4-fluorophenyl)sulfonamido)methyl)-N-((2-methylthiazol-5-yl)methyl)pyrazine-2-carboxamide) and MPX-007 (5-(((3-fluoro-4-fluorophenyl)sulfonamido)methyl)-N-((2-methylthiazol-5-yl)methyl)methylpyrazine-2-carboxamide). MPX-004 and MPX-007 inhibit GluN2A-containing NMDA receptors expressed in HEK cells with IC50s of 79 nM and 27 nM, respectively. In contrast, at concentrations that completely inhibited GluN2A activity these compounds have no inhibitory effect on GluN2B or GluN2D receptor-mediated responses in similar HEK cell-based assays. Potency and selectivity were confirmed in electrophysiology assays in Xenopus oocytes expressing GluN2A-D receptor subtypes. Maximal concentrations of MPX-004 and MPX-007 inhibited ~30% of the whole-cell current in rat pyramidal neurons in primary culture and MPX-004 inhibited ~60% of the total NMDA receptor-mediated EPSP in rat hippocampal slices. GluN2A-selectivity at native receptors was confirmed by the finding that MPX-004 had no inhibitory effect on NMDA receptor mediated synaptic currents in cortical slices from GRIN2A knock out mice. Thus, MPX-004 and MPX-007 offer highly selective pharmacological tools to probe GluN2A physiology and involvement in neuropsychiatric and developmental disorders. |
| Databáze: | OpenAIRE |
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