{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,25]],"date-time":"2026-02-25T01:43:01Z","timestamp":1771983781878,"version":"3.50.1"},"reference-count":40,"publisher":"Wiley","license":[{"start":{"date-parts":[[2025,3,29]],"date-time":"2025-03-29T00:00:00Z","timestamp":1743206400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Chemistry &amp; Biodiversity"],"abstract":"<jats:title>ABSTRACT<\/jats:title><jats:p>\u03b1\u2010Amino\u20103\u2010hydroxy\u20105\u2010methyl\u20104\u2010isoxazole\u2010propionic acid (AMPA) receptors, especially GluA2\u2010containing 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\u2010isoxazole\u2010carboxamide (ISX) derivatives, including ISX\u20101 and its analogs, as modulators of GluA2\u2010containing AMPAR activity. These were synthesized and then characterized to be used to effectively modulate AMPAR kinetics using advanced electrophysiological techniques in HEK293T cells. ISX\u201011 exhibited the most potent inhibitory effect among the tested compounds, reducing GluA2 and GluA2\/3 currents (<jats:italic>p<\/jats:italic> &lt; 0.001), with IC<jats:sub>50<\/jats:sub> values of 4.4 and 4.62\u00a0\u00b5M, respectively. ISX\u20108 also showed significant inhibition (<jats:italic>p<\/jats:italic> &lt; 0.001), with IC<jats:sub>50<\/jats:sub> values of 4.6 and 4.79\u00a0\u00b5M. Additionally, ISX\u201011 and ISX\u20108 significantly increased deactivation rates by 2.5\u2010 and 2\u2010fold, respectively, while decreasing desensitization rates by similar magnitudes. Fluorophenyl, methoxy, and <jats:italic>tert<\/jats:italic>\u2010butyl 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.<\/jats:p>","DOI":"10.1002\/cbdv.202500392","type":"journal-article","created":{"date-parts":[[2025,3,18]],"date-time":"2025-03-18T08:00:26Z","timestamp":1742284826000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Isoxazole\u2010Carboxamide Modulators of GluA2\u2010Containing \u03b1\u2010Amino\u20103\u2010hydroxy\u20105\u2010methyl\u20104\u2010isoxazole\u2010propionic Acid Receptors in Parkinson's Disease"],"prefix":"10.1002","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0702-7834","authenticated-orcid":false,"given":"Mohammad","family":"Qneibi","sequence":"first","affiliation":[{"name":"Department of Biomedical Sciences Faculty of Medicine and Health Sciences An\u2010Najah National University  Nablus Palestine"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2025,3,29]]},"reference":[{"issue":"3","key":"e_1_2_10_2_1","doi-asserted-by":"crossref","first-page":"464","DOI":"10.3390\/biom10030464","article-title":"Ionotropic Glutamate Receptors in Epilepsy: A Review Focusing on AMPA and NMDA Receptors","volume":"10","author":"Hanada T.","year":"2020","journal-title":"Biomolecules"},{"key":"e_1_2_10_3_1","volume-title":"The Ionotropic Glutamate Receptors","author":"Monaghan D. 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