Isoxazole-Carboxamide Modulators of GluA2-Containing α-Amino-3-hydroxy-5-methyl-4-isoxazole-propionic Acid Receptors in Parkinson's Disease

α-Amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid (AMPA) receptors, especially GluA2-containing subunits, play a pivotal role in minimizing calcium permeability and excitotoxicity as part of the critical developments in the pathogenesis of Parkinson's disease (PD). AMPA receptor (AMPAR) modulation has been considered one promising therapeutic avenue to counteract glutamate neurotoxicity. The present study explored the potential of fluorophenyl-isoxazole-carboxamide (ISX) derivatives, including ISX-1 and its analogs, as modulators of GluA2-containing AMPAR activity. These were synthesized and then characterized to be used to effectively modulate AMPAR kinetics using advanced electrophysiological techniques in HEK293T cells. ISX-11 exhibited the most potent inhibitory effect among the tested compounds, reducing GluA2 and GluA2/3 currents (p < 0.001), with IC₅₀ values of 4.4 and 4.62 µM, respectively. ISX-8 also showed significant inhibition (p < 0.001), with IC₅₀ values of 4.6 and 4.79 µM. Additionally, ISX-11 and ISX-8 significantly increased deactivation rates by 2.5- and 2-fold, respectively, while decreasing desensitization rates by similar magnitudes. Fluorophenyl, methoxy, and tert-butyl substituents have been most important in achieving excellent pharmacodynamic and pharmacokinetic properties for AMPA modulators. This report supplements earlier reports on how the structure can affect the activity of various isoxazole derivatives, displaying reduced excitotoxic injury to nigrostriatal dopaminergic neurons relevant to PD.