Abstract
Starting from 1-4 and 7 structural templates, analogues based on bioisosteric replacements (5a-c vs 1, 2 and 6 vs 7) were synthesized for completing the SAR analysis. Interesting binding properties at GluA2, GluK1, and GluK3 receptors were discovered. The requirements for GluK3 interaction were elucidated by determining the X-ray structures of the GluK3-LBD with 2 and 5c and by computational studies. Antinociceptive potential was demonstrated for GluK1 partial agonist 3 and antagonist 7 (2 mg/kg ip).
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Analgesics / chemistry
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Animals
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Crystallography, X-Ray
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GluK3 Kainate Receptor
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Ligands
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Protein Binding
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Receptors, AMPA
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Receptors, Kainic Acid / agonists
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Receptors, Kainic Acid / antagonists & inhibitors
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Receptors, Kainic Acid / chemistry*
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Receptors, Kainic Acid / metabolism
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Structure-Activity Relationship
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alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid / analogs & derivatives*
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alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid / chemistry
Substances
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Analgesics
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Gluk1 kainate receptor
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Ligands
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Receptors, AMPA
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Receptors, Kainic Acid
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alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid