(S)-2-Amino-3-(5-methyl-3-hydroxyisoxazol-4-yl)propanoic Acid (AMPA) and Kainate Receptor Ligands: Further Exploration of Bioisosteric Replacements, Structural and Biological Investigation.

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 SAP. analysis. Interesting binding properties at GluA2, G1uK1, and G1uK3 receptors were discovered. The requirements for G1uK3 interaction were elucidated by determining the X-ray structures of the GluK3-LBD with 2 and Sc and by computational studies. Antinociceptive potential was demonstrated for GluK1 partial agonist 3 and antagonist 7 (2 mg/kg ip).