Isoxazolo[3,4-d]pyridazinones positively modulate the metabotropic glutamate subtypes 2 and 4
| Autor: | Chris Koerner, Donald S. Backos, Hye Jin Kang, Philip Reigan, Joseph Mirzaei, Nicholas R. Natale, Christina Gates |
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| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
animal structures Stereochemistry Clinical Biochemistry Allosteric regulation Pharmaceutical Science Receptors Metabotropic Glutamate Biochemistry Article Structure-Activity Relationship 03 medical and health sciences chemistry.chemical_compound Allosteric Regulation mental disorders Drug Discovery Animals Molecular Biology Fenobam Chemistry Metabotropic glutamate receptor 5 musculoskeletal neural and ocular physiology Organic Chemistry Isoxazoles nervous system diseases Pyridazines 030104 developmental biology Metabotropic receptor nervous system Metabotropic glutamate receptor Molecular Medicine NMDA receptor Metabotropic glutamate receptor 1 Metabotropic glutamate receptor 2 |
| Zdroj: | Bioorganic & Medicinal Chemistry. 26:4797-4803 |
| ISSN: | 0968-0896 |
| Popis: | Isoxazolo[3,4-d] pyridazinones ([3,4-d]s) are selective positive modulators of the metabotropic glutamate receptors (mGluRs) subtypes 2 and 4, with no functional cross reactivity at mGluR(1a), mGLuR(5) or mGluR(8). Modest binding for two of the [3,4-d]s is observed at the allosteric fenobam mGluR(5) site, but not sufficient to translate into a functional effect. The structure activity relationship (SAR) for mGluR(2) and mGluR(4) are distinct: the compounds which select for mGluR(2) all contain fluorine on the N-6 aryl group. Furthermore, the [3,4-d]s in this study showed no significant binding at inhibitory GABA(A,) nor excitatory NMDA receptors, and previously we had disclosed that they lack significant activity at the System Xc- Antiporter. A homology model based on Conn’s mGluR(1) crystal structure was examined, and suggested explanations for a preference for allosteric over orthosteric binding, subtype selectivity, and suggested avenues for optimization of efficacy as a reasonable working hypothesis. |
| Databáze: | OpenAIRE |
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