{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,12]],"date-time":"2026-11-12T05:44:39Z","timestamp":1794462279380,"version":"4.9.1"},"reference-count":34,"publisher":"American Chemical Society (ACS)","issue":"37","license":[{"start":{"date-parts":[[2026,9,10]],"date-time":"2026-09-10T00:00:00Z","timestamp":1788998400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100004836","name":"Danmarks Frie Forskningsfond","doi-asserted-by":"publisher","award":["0134-00162B"],"award-info":[{"award-number":["0134-00162B"]}],"id":[{"id":"10.13039\/501100004836","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100006673","name":"Fonds L?on Fredericq","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100006673","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100002661","name":"Fonds De La Recherche Scientifique - FNRS","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100002661","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2026,9,22]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Kainate-type ionotropic glutamate receptors (KARs) are emerging therapeutic targets for the modulation of excitatory neurotransmission in epilepsy, psychiatric disorders, and neurodegenerative diseases, yet selective positive allosteric modulators (PAMs) remain scarce. Starting from the benzothiadiazine AMPA receptor (AMPAR) PAM BPAM344 (1), we pursued a structure-based scaffold repurposing strategy to identify KAR-directed analogues. A focused library of benzothiadiazine 1,1-dioxides (7a\u20137z) was designed through systematic diversification at the N4 position and modulation of the C7 substituent (H, F, and Cl). Compounds were synthesized via a convergent route involving benzothiadiazine core assembly, N4 alkylation with aliphatic (including nitrile-terminated), trifluorinated, benzyl, or phenethyl substituents, followed by reduction to the corresponding 3,4-dihydro derivatives. All compounds were fully characterized and evaluated for modulatory activity at GluA2 and GluK1\u20133 receptors using Ca2+ fluorescence assays in HEK cells. Clear structure\u2013activity relationships (SAR) were established. Short nitrile-terminated aliphatic substituents (7a\u20137g) retained GluA2 potentiation but lacked KAR activity, indicating that flexible polar chains favor AMPAR selectivity. In contrast, the N4-benzyl series revealed a more complex structure\u2013activity relationship. The para-nitro benzyl analogue 7y was inactive across the receptor subtypes tested, whereas the 3-fluoro-4-nitrobenzyl derivative 7q showed preferential potentiation of GluK1 and GluK3, with minimal GluA2 modulation. Notably, the meta-fluorinated benzyl analogue 7u preferentially potentiated GluK3 while remaining inactive at GluK1, GluK2, and GluA2, whereas the other fluorinated derivatives were devoid of detectable activity across the receptor subtypes tested. These findings reveal a distinct subtype-dependent SAR and support the existence of a spatially constrained polar microenvironment within the GluK1\/3 allosteric sites, which appears to be optimally engaged by rigid para-polar benzyl substituents. In line with our docking observations, acidic substituents may further exploit this polar region while the core scaffold remains favorably accommodated in the surrounding hydrophobic pocket. On the basis of the pharmacological testing, meta-fluorination appears to further refine subtype selectivity toward GluK3 and may represent a promising starting point for further exploratory work. Collectively, these results establish 1,2,4-benzothiadiazine 1,1-dioxides as a tractable chemotype for the development of subtype-selective KAR PAMs and provide a medicinal chemistry framework for second-generation optimization, while the docking-derived contacts should be regarded as plausible structural hypotheses rather than experimentally confirmed interactions, given that they are based on SwissDock-predicted poses rather than a crystallographic ligand\u2013receptor complex.<\/jats:p>","DOI":"10.1021\/acsomega.6c03618","type":"journal-article","created":{"date-parts":[[2026,9,10]],"date-time":"2026-09-10T09:01:34Z","timestamp":1789030894000},"page":"55299-55315","source":"Crossref","is-referenced-by-count":1,"title":["Design and Evaluation of Selective Positive Allosteric\nModulators Targeting Kainate Receptors"],"prefix":"10.1021","volume":"11","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4828-1289","authenticated-orcid":true,"given":"Thomas","family":"Colson","sequence":"first","affiliation":[{"name":"University of Lie\u0300ge , , Building B36, Level +5, Avenue Hippocrate 15 , ,","place":["Lie\u0300ge, Belgium, B-4000"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yasmin","family":"Bay","sequence":"additional","affiliation":[{"name":"University of Copenhagen , , Universitetsparken 2 , ,","place":["Copenhagen, Denmark, 2100"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexandra","family":"Manos-Turvey","sequence":"additional","affiliation":[{"name":"University of Lie\u0300ge , , Building B36, Level +5, Avenue Hippocrate 15 , ,","place":["Lie\u0300ge, Belgium, B-4000"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giacomo","family":"Baudino","sequence":"additional","affiliation":[{"name":"University of Lie\u0300ge , , Building B36, Level +5, Avenue Hippocrate 15 , ,","place":["Lie\u0300ge, Belgium, B-4000"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bastiaan","family":"Poldermans","sequence":"additional","affiliation":[{"name":"University of Copenhagen , , Universitetsparken 2 , ,","place":["Copenhagen, Denmark, 2100"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eric","family":"Goffin","sequence":"additional","affiliation":[{"name":"University of Lie\u0300ge , , Building B36, Level +5, Avenue Hippocrate 15 , ,","place":["Lie\u0300ge, Belgium, B-4000"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marine","family":"Piette","sequence":"additional","affiliation":[{"name":"University of Lie\u0300ge , , Building B36, Level +5, Avenue Hippocrate 15 , ,","place":["Lie\u0300ge, Belgium, B-4000"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cindy","family":"Lesenfants","sequence":"additional","affiliation":[{"name":"University of Lie\u0300ge , , Building B36, Level +5, Avenue Hippocrate 15 , ,","place":["Lie\u0300ge, Belgium, B-4000"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marie","family":"Leclercq","sequence":"additional","affiliation":[{"name":"University of Lie\u0300ge , , Building B36, Level +5, Avenue Hippocrate 15 , ,","place":["Lie\u0300ge, Belgium, B-4000"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2654-1510","authenticated-orcid":true,"given":"Jette S.","family":"Kastrup","sequence":"additional","affiliation":[{"name":"University of Copenhagen , , Universitetsparken 2 , ,","place":["Copenhagen, Denmark, 2100"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bernard","family":"Pirotte","sequence":"additional","affiliation":[{"name":"University of Lie\u0300ge , , Building B36, Level +5, Avenue Hippocrate 15 , ,","place":["Lie\u0300ge, Belgium, B-4000"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8955-6790","authenticated-orcid":true,"given":"Anders S.","family":"Kristensen","sequence":"additional","affiliation":[{"name":"University of Copenhagen , , Universitetsparken 2 , ,","place":["Copenhagen, Denmark, 2100"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9252-7798","authenticated-orcid":true,"given":"Pierre","family":"Francotte","sequence":"additional","affiliation":[{"name":"University of Lie\u0300ge , , Building B36, Level +5, Avenue Hippocrate 15 , ,","place":["Lie\u0300ge, Belgium, B-4000"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"316","published-online":{"date-parts":[[2026,9,10]]},"reference":[{"issue":"3","key":"2026092211412508300_cit1","doi-asserted-by":"publisher","first-page":"239","DOI":"10.2174\/157488906778773661","article-title":"In Search of Novel AMPA 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Ther. Pat."},{"issue":"4","key":"2026092211412508300_cit3","doi-asserted-by":"publisher","first-page":"1469","DOI":"10.1124\/pharmrev.120.000131","article-title":"Structure\nFunction, and Pharmacology of Glutamate Receptor Ion Channels","volume":"73","author":"Hansen","year":"2021","journal-title":"Pharmacol. Rev."},{"issue":"7274","key":"2026092211412508300_cit4","doi-asserted-by":"publisher","first-page":"745","DOI":"10.1038\/nature08624","article-title":"X-Ray Structure, Symmetry and Mechanism\nof an AMPA-Subtype Glutamate Receptor","volume":"462","author":"Sobolevsky","year":"2009","journal-title":"Nature"},{"issue":"3","key":"2026092211412508300_cit5","doi-asserted-by":"publisher","first-page":"405","DOI":"10.1124\/pr.109.002451","article-title":"Glutamate Receptor Ion Channels: Structure, Regulation,\nand Function","volume":"62","author":"Traynelis","year":"2010","journal-title":"Pharmacol. Rev."},{"issue":"6","key":"2026092211412508300_cit6","doi-asserted-by":"publisher","first-page":"576","DOI":"10.1124\/mol.116.107599","article-title":"Identification and\nStructure-Function Study of Positive Allosteric Modulators of Kainate\nReceptors","volume":"91","author":"Larsen","year":"2017","journal-title":"Mol. Pharmacol"},{"issue":"4","key":"2026092211412508300_cit7","doi-asserted-by":"publisher","first-page":"713","DOI":"10.1016\/j.neuron.2017.04.009","article-title":"Structural and Functional Architecture\nof AMPA-Type Glutamate Receptors and Their Auxiliary Proteins","volume":"94","author":"Greger","year":"2017","journal-title":"Neuron"},{"issue":"6438","key":"2026092211412508300_cit8","doi-asserted-by":"publisher","first-page":"355","DOI":"10.1126\/science.aaw8250","article-title":"Architecture\nand Subunit Arrangement of Native AMPA Receptors Elucidated by Cryo-EM","volume":"364","author":"Zhao","year":"2019","journal-title":"Science"},{"issue":"2","key":"2026092211412508300_cit9","doi-asserted-by":"publisher","first-page":"453","DOI":"10.1113\/JP278701","article-title":"AMPA Receptor Structure and Auxiliary Subunits","volume":"599","author":"Kamalova","year":"2021","journal-title":"J. Physiol."},{"issue":"2","key":"2026092211412508300_cit10","doi-asserted-by":"publisher","first-page":"292","DOI":"10.1016\/j.neuron.2013.09.045","article-title":"Kainate Receptors in Health and Disease","volume":"80","author":"Lerma","year":"2013","journal-title":"Neuron"},{"issue":"2","key":"2026092211412508300_cit11","doi-asserted-by":"publisher","first-page":"457","DOI":"10.1007\/s00441-006-0265-6","article-title":"Kainate Receptors","volume":"326","author":"Pinheiro","year":"2006","journal-title":"Cell Tissue Res."},{"issue":"2","key":"2026092211412508300_cit12","doi-asserted-by":"publisher","first-page":"181","DOI":"10.1113\/JP280873","article-title":"Structural Basis for Positive Allosteric\nModulation of AMPA and Kainate Receptors","volume":"600","author":"Frydenvang","year":"2022","journal-title":"J.\nPhys."},{"issue":"9","key":"2026092211412508300_cit13","doi-asserted-by":"publisher","first-page":"1582","DOI":"10.1016\/j.str.2016.06.019","article-title":"The Structure of a High-Affinity\nKainate Receptor: GluK4 Ligand-Binding Domain Crystallized with Kainate","volume":"24","author":"Kristensen","year":"2016","journal-title":"Structure"},{"issue":"2","key":"2026092211412508300_cit14","doi-asserted-by":"publisher","first-page":"249","DOI":"10.1113\/jphysiol.2003.054320","article-title":"Structure\nand Function of AMPA Receptors","volume":"554","author":"Gouaux","year":"2004","journal-title":"J. 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Neurosci."},{"issue":"4976","key":"2026092211412508300_cit16","doi-asserted-by":"publisher","first-page":"1580","DOI":"10.1126\/science.1699275","article-title":"Flip and Flop: A Cell-Specific Functional Switch in\nGlutamate-Operated Channels of the CNS","volume":"249","author":"Sommer","year":"1990","journal-title":"Science"},{"issue":"17","key":"2026092211412508300_cit17","doi-asserted-by":"publisher","first-page":"3767","DOI":"10.1021\/bi8015907","article-title":"Flip and Flop: A Molecular Determinant for AMPA Receptor Channel\nOpening","volume":"48","author":"Pei","year":"2009","journal-title":"Biochemistry"},{"issue":"19","key":"2026092211412508300_cit18","doi-asserted-by":"publisher","first-page":"4138","DOI":"10.1016\/j.febslet.2005.06.044","article-title":"ASF\/SF2 and SC35 Regulate the Glutamate Receptor Subunit\n2 Alternative Flip\/Flop Splicing","volume":"579","author":"Crovato","year":"2005","journal-title":"FEBS Lett."},{"issue":"2","key":"2026092211412508300_cit19","doi-asserted-by":"publisher","first-page":"525","DOI":"10.1007\/s00424-010-0809-1","article-title":"Glutamate Receptors, Neurotoxicity and Neurodegeneration","volume":"460","author":"Lau","year":"2010","journal-title":"Pflu\u0308g. Arch. - Eur. J. Physiol."},{"issue":"2","key":"2026092211412508300_cit20","doi-asserted-by":"publisher","first-page":"91","DOI":"10.1038\/nrn725","article-title":"The Structure\nand Function of Glutamate Receptor Ion Channels","volume":"3","author":"Madden","year":"2002","journal-title":"Nat. Rev. Neurosci."},{"issue":"6560","key":"2026092211412508300_cit21","doi-asserted-by":"publisher","first-page":"78","DOI":"10.1038\/379078a0","article-title":"Regulation of Glutamate Release by Presynaptic Kainate\nReceptors in the Hippocampus","volume":"379","author":"Chittajallu","year":"1996","journal-title":"Nature"},{"issue":"6638","key":"2026092211412508300_cit22","doi-asserted-by":"publisher","first-page":"182","DOI":"10.1038\/40645","article-title":"Kainate Receptors Mediate a Slow\nPostsynaptic Current in Hippocampal CA3 Neurons","volume":"388","author":"Castillo","year":"1997","journal-title":"Nature"},{"issue":"6638","key":"2026092211412508300_cit23","doi-asserted-by":"publisher","first-page":"179","DOI":"10.1038\/40639","article-title":"The Synaptic Activation of Kainate Receptors","volume":"388","author":"Vignes","year":"1997","journal-title":"Nature"},{"issue":"11","key":"2026092211412508300_cit24","doi-asserted-by":"publisher","first-page":"1609","DOI":"10.3390\/biom13111609","article-title":"Glutamate Receptor Dysregulation and Platelet Glutamate Dynamics\nin Alzheimer\u2019s and Parkinson\u2019s Diseases: Insights into\nCurrent Medications","volume":"13","author":"Gautam","year":"2023","journal-title":"Biomolecules"},{"issue":"2","key":"2026092211412508300_cit25","doi-asserted-by":"publisher","first-page":"403","DOI":"10.1021\/acs.jmedchem.8b00714","article-title":"Positron\nEmission Tomography (PET) Ligand Development for Ionotropic Glutamate\nReceptors: Challenges and Opportunities for Radiotracer Targeting N -Methyl- d -Aspartate (NMDA), \u03b1-Amino-3-Hydroxy-5-Methyl-4-Isoxazolepropionic\nAcid (AMPA), and Kainate Receptors: Miniperspective","volume":"62","author":"Fu","year":"2019","journal-title":"J. Med. Chem."},{"issue":"1","key":"2026092211412508300_cit26","doi-asserted-by":"publisher","first-page":"7","DOI":"10.1016\/j.expneurol.2008.01.011","article-title":"The Role of AMPA Receptor Modulation in the Treatment\nof Neuropsychiatric Diseases","volume":"211","author":"Zarate","year":"2008","journal-title":"Exp. Neurol."},{"key":"2026092211412508300_cit27","doi-asserted-by":"publisher","first-page":"237","DOI":"10.1016\/j.neuroscience.2012.06.002","article-title":"Hippocampal Tissue of Patients with\nRefractory Temporal Lobe Epilepsy Is Associated with Astrocyte Activation,\nInflammation, and Altered Expression of Channels and Receptors","volume":"220","author":"Das","year":"2012","journal-title":"Neurosci."},{"issue":"40","key":"2026092211412508300_cit28","doi-asserted-by":"publisher","first-page":"13619","DOI":"10.1523\/JNEUROSCI.2217-15.2015","article-title":"Increased\nDosage of High-Affinity Kainate Receptor Gene Grik4 Alters Synaptic Transmission and Reproduces Autism Spectrum Disorders\nFeatures","volume":"35","author":"Aller","year":"2015","journal-title":"J. Neurosci."},{"issue":"1","key":"2026092211412508300_cit29","doi-asserted-by":"publisher","first-page":"30","DOI":"10.1016\/j.schres.2015.11.008","article-title":"Genetic\nAssessment of Additional Endophenotypes from the Consortium on the\nGenetics of Schizophrenia Family Study","volume":"170","author":"Greenwood","year":"2016","journal-title":"Schizophr.\nRes."},{"issue":"2","key":"2026092211412508300_cit30","doi-asserted-by":"publisher","first-page":"406","DOI":"10.1016\/j.bbr.2011.12.026","article-title":"Genetic Ablation of the GluK4 Kainate Receptor Subunit\nCauses Anxiolytic and Antidepressant-like Behavior in Mice","volume":"228","author":"Catches","year":"2012","journal-title":"Behav Brain Res."},{"issue":"13","key":"2026092211412508300_cit31","doi-asserted-by":"publisher","first-page":"3153","DOI":"10.1021\/jm070120i","article-title":"Design, Synthesis,\nand Pharmacology of Novel 7-Substituted 3,4-Dihydro-2 H \u22121,2,4-Benzothiadiazine 1,1-Dioxides as Positive Allosteric\nModulators of AMPA Receptors","volume":"50","author":"Francotte","year":"2007","journal-title":"J. Med. Chem."},{"issue":"21","key":"2026092211412508300_cit32","doi-asserted-by":"publisher","first-page":"8736","DOI":"10.1021\/jm4012092","article-title":"Pharmacological\nand Structural Characterization, and Thermodynamic Aspects of GluA2-Positive\nAllosteric Modulators with a 3,4-Dihydro-2 H \u22121,2,4-Benzothiadiazine\n1,1-Dioxide Scaffold","volume":"56","author":"N\u00f8rholm","year":"2013","journal-title":"J. Med. Chem."},{"issue":"1","key":"2026092211412508300_cit33","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1080\/00304940903507788","article-title":"Arylcyclopropanes: Properties, Synthesis\nand Use in Medicinal Chemistry","volume":"42","author":"Gagnon","year":"2010","journal-title":"Org. Prep. Proced.\nInt."},{"issue":"7","key":"2026092211412508300_cit34","doi-asserted-by":"publisher","first-page":"1506","DOI":"10.1111\/febs.17046","article-title":"Small-molecule Positive Allosteric\nModulation of Homomeric Kainate Receptors GluK1 \u22123: Development\nof Screening Assays and Insight into GluK3 Structure","volume":"291","author":"Bay","year":"2024","journal-title":"FEBS J."}],"container-title":["ACS Omega"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/pubs.acs.org\/doi\/pdf\/10.1021\/acsomega.6c03618","content-type":"application\/pdf","content-version":"vor","intended-application":"unspecified"},{"URL":"https:\/\/pubs.acs.org\/acsodf\/article-pdf\/11\/37\/55299\/68467832\/acsomega.6c03618.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/pubs.acs.org\/acsodf\/article-pdf\/11\/37\/55299\/68467832\/acsomega.6c03618.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,9,22]],"date-time":"2026-09-22T15:49:53Z","timestamp":1790092193000},"score":1,"resource":{"primary":{"URL":"https:\/\/pubs.acs.org\/acsodf\/article\/11\/37\/55299\/5427477\/Design-and-Evaluation-of-Selective-Positive"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,9,10]]},"references-count":34,"journal-issue":{"issue":"37","published-online":{"date-parts":[[2026,9,10]]},"published-print":{"date-parts":[[2026,9,22]]}},"URL":"https:\/\/doi.org\/10.1021\/acsomega.6c03618","relation":{"has-part":[{"id-type":"doi","id":"https:\/\/doi.org\/10.1021\/acsomega.6c03618.s001","asserted-by":"subject"}]},"ISSN":["2470-1343"],"issn-type":[{"value":"2470-1343","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,9,10]]}}}