α-Amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid (AMPA) receptors, especially GluA2-containing subunits, play a pivotalrole in minimizing calcium permeability and excitotoxicity as part of the critical developments in the pathogenesis of Parkinson’sdisease (PD). AMPA receptor (AMPAR) modulation has been considered one promising therapeutic avenue to counteractglutamate 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 thencharacterized to be used to effectively modulate AMPAR kinetics using advanced electrophysiological techniques in HEK293Tcells. 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 IC50values 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 beenmost important in achieving excellent pharmacodynamic and pharmacokinetic properties for AMPA modulators. This reportsupplements earlier reports on how the structure can affect the activity of various isoxazole derivatives, displaying reducedexcitotoxic injury to nigrostriatal dopaminergic neurons relevant to PD.

العنوان

Chemistry and Biodiversity

الناشر

Wiley

بلد الناشر

ألمانيا

Indexing

Thomson Reuters

معامل التأثير

2,3

نوع المنشور

مطبوع فقط

المجلد

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السنة

2025

الصفحات

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