Article ; Online: Discovery of Pyrazolo[1,5-a]pyrazin-4-ones as Potent and Brain Penetrant GluN2A-Selective Positive Allosteric Modulators Reducing AMPA Receptor Binding Activity.
Bioorganic & medicinal chemistry
2021 Volume 56, Page(s) 116576
Abstract: N-Methyl-d-aspartate receptors (NMDARs) are members of the ionotropic glutamate receptor family and play a crucial role in learning and memory by regulating synaptic plasticity. Activation of NMDARs containing GluN2A, one of the NMDAR subunits, has ... ...
| Abstract | N-Methyl-d-aspartate receptors (NMDARs) are members of the ionotropic glutamate receptor family and play a crucial role in learning and memory by regulating synaptic plasticity. Activation of NMDARs containing GluN2A, one of the NMDAR subunits, has recently attracted attention as a promising therapeutic approach for neuropsychiatric diseases such as schizophrenia, depression, and epilepsy. In the present study, we developed potent and brain-penetrable GluN2A-selective positive allosteric modulators. Lead compound 2b was generated by scaffold hopping of hit compound 1, identified from the internal alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR)-focused compound library through a high-throughput screening campaign. Subsequent optimization of the lead compound, including a structure-based drug design approach, resulted in the identification of a potent GluN2A PAM (R)-9, which possessed high selectivity against both subtypes of AMPAR and NMDAR. Furthermore, (R)-9 significantly enhanced long-term potentiation in the rat hippocampus 24 h after oral administration, indicating that this molecule is a potentially useful in vivo pharmacological tool for treating psychiatric diseases. |
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| MeSH term(s) | Administration, Oral ; Allosteric Regulation/drug effects ; Animals ; Binding Sites/drug effects ; Brain/metabolism ; Crystallography, X-Ray ; Dose-Response Relationship, Drug ; Drug Discovery ; Injections, Intravenous ; Male ; Molecular Docking Simulation ; Molecular Structure ; Rats ; Rats, Sprague-Dawley ; Receptors, AMPA/metabolism ; Receptors, N-Methyl-D-Aspartate/metabolism ; Structure-Activity Relationship |
| Chemical Substances | Receptors, AMPA ; Receptors, N-Methyl-D-Aspartate ; N-methyl D-aspartate receptor subtype 2A (VH92ICR8HX) |
| Language | English |
| Publishing date | 2021-12-16 |
| Publishing country | England |
| Document type | Journal Article |
| ZDB-ID | 1161284-8 |
| ISSN | 1464-3391 ; 0968-0896 |
| ISSN (online) | 1464-3391 |
| ISSN | 0968-0896 |
| DOI | 10.1016/j.bmc.2021.116576 |
| Database | MEDical Literature Analysis and Retrieval System OnLINE |
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