{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,14]],"date-time":"2026-10-14T16:44:38Z","timestamp":1791996278967,"version":"4.4.0"},"reference-count":144,"publisher":"MDPI AG","issue":"13","license":[{"start":{"date-parts":[[2025,6,25]],"date-time":"2025-06-25T00:00:00Z","timestamp":1750809600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"National Research, Development, and Innovation Office","award":["K138125"],"award-info":[{"award-number":["K138125"]}]},{"name":"National Research, Development, and Innovation Office","award":["2022\/5S729"],"award-info":[{"award-number":["2022\/5S729"]}]},{"name":"National Research, Development, and Innovation Office","award":["TKP-2021-EGA-32"],"award-info":[{"award-number":["TKP-2021-EGA-32"]}]},{"name":"National Research, Development, and Innovation Office","award":["\u00daNKP-22-4-SZTE-166"],"award-info":[{"award-number":["\u00daNKP-22-4-SZTE-166"]}]},{"name":"HUN-REN Hungarian Research Network","award":["K138125"],"award-info":[{"award-number":["K138125"]}]},{"name":"HUN-REN Hungarian Research Network","award":["2022\/5S729"],"award-info":[{"award-number":["2022\/5S729"]}]},{"name":"HUN-REN Hungarian Research Network","award":["TKP-2021-EGA-32"],"award-info":[{"award-number":["TKP-2021-EGA-32"]}]},{"name":"HUN-REN Hungarian Research Network","award":["\u00daNKP-22-4-SZTE-166"],"award-info":[{"award-number":["\u00daNKP-22-4-SZTE-166"]}]},{"name":"Ministry of Human Capacities, Hungary","award":["K138125"],"award-info":[{"award-number":["K138125"]}]},{"name":"Ministry of Human Capacities, Hungary","award":["2022\/5S729"],"award-info":[{"award-number":["2022\/5S729"]}]},{"name":"Ministry of Human Capacities, Hungary","award":["TKP-2021-EGA-32"],"award-info":[{"award-number":["TKP-2021-EGA-32"]}]},{"name":"Ministry of Human Capacities, Hungary","award":["\u00daNKP-22-4-SZTE-166"],"award-info":[{"award-number":["\u00daNKP-22-4-SZTE-166"]}]},{"name":"New National Excellence Program of the Ministry for Culture and Innovation","award":["K138125"],"award-info":[{"award-number":["K138125"]}]},{"name":"New National Excellence Program of the Ministry for Culture and Innovation","award":["2022\/5S729"],"award-info":[{"award-number":["2022\/5S729"]}]},{"name":"New National Excellence Program of the Ministry for Culture and Innovation","award":["TKP-2021-EGA-32"],"award-info":[{"award-number":["TKP-2021-EGA-32"]}]},{"name":"New National Excellence Program of the Ministry for Culture and Innovation","award":["\u00daNKP-22-4-SZTE-166"],"award-info":[{"award-number":["\u00daNKP-22-4-SZTE-166"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>Kynurenic acid (KYNA), a putative neuroprotective agent, modulates glutamatergic pathways in schizophrenia and Parkinson\u2019s disease but is limited by acute motor activity impairments (e.g., ataxia). Research leveraging animal disease models explores its structure\u2013activity relationship to enhance therapeutic efficacy while mitigating adverse effects, addressing global neuropsychiatric disorders affecting over 1 billion people. Structural analogs of KYNA (SZR-72, SZR-73, and SZR-81) were designed to uncouple therapeutic benefits from motor toxicity; yet, systematic comparisons of their acute behavioral profiles remain unexplored. Here, we assess the motor safety, time-dependent effects, and therapeutic potential of these analogs in mice. Using acute intracerebroventricular dosing, we evaluated motor coordination (rotarod), locomotor activity (open-field), and stereotypic behaviors. KYNA induced significant ataxia and stereotypic behaviors at 15 min, resolving by 45 min. In contrast, all analogs avoided acute motor deficits, with SZR-73 maintaining baseline rotarod performance and eliciting a delayed decrease in ambulation and inquisitiveness in open-field assays. These findings demonstrate that the structural optimization of KYNA successfully mitigates motor toxicity while retaining neuromodulatory activity. Here, we show that SZR-73 emerges as a lead candidate, combining transient therapeutic effects with preserved motor coordination. This study advances the development of safer neuroactive compounds, bridging a critical gap between preclinical innovation and clinical translation. Future work must validate chronic efficacy, disease relevance, and mechanistic targets to harness the full potential of KYNA analogs in treating complex neuropsychiatric disorders.<\/jats:p>","DOI":"10.3390\/cells14130973","type":"journal-article","created":{"date-parts":[[2025,6,25]],"date-time":"2025-06-25T03:53:02Z","timestamp":1750823582000},"page":"973","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Decoupling Behavioral Domains via Kynurenic Acid Analog Optimization: Implications for Schizophrenia and Parkinson\u2019s Disease Therapeutics"],"prefix":"10.3390","volume":"14","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-7596-9965","authenticated-orcid":false,"given":"Di\u00e1na","family":"Martos","sequence":"first","affiliation":[{"name":"HUN-REN-SZTE Neuroscience Research Group, Hungarian Research Network, University of Szeged Danube Neuroscience Research Laboratory, Tisza Lajos krt. 113, H-6725 Szeged, Hungary"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7773-0034","authenticated-orcid":false,"given":"B\u00e1lint","family":"L\u0151rinczi","sequence":"additional","affiliation":[{"name":"Institute of Pharmaceutical Chemistry and HUN-REN-SZTE Stereochemistry Research Group, University of Szeged, E\u00f6tv\u00f6s u. 6, H-6720 Szeged, Hungary"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8571-5229","authenticated-orcid":false,"given":"Istv\u00e1n","family":"Szatm\u00e1ri","sequence":"additional","affiliation":[{"name":"Institute of Pharmaceutical Chemistry and HUN-REN-SZTE Stereochemistry Research Group, University of Szeged, E\u00f6tv\u00f6s u. 6, H-6720 Szeged, Hungary"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"L\u00e1szl\u00f3","family":"V\u00e9csei","sequence":"additional","affiliation":[{"name":"HUN-REN-SZTE Neuroscience Research Group, Hungarian Research Network, University of Szeged Danube Neuroscience Research Laboratory, Tisza Lajos krt. 113, H-6725 Szeged, Hungary"},{"name":"Department of Neurology, Albert Szent-Gy\u00f6rgyi Medical School, University of Szeged, Semmelweis u. 6, H-6725 Szeged, Hungary"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4383-4024","authenticated-orcid":false,"given":"Masaru","family":"Tanaka","sequence":"additional","affiliation":[{"name":"HUN-REN-SZTE Neuroscience Research Group, Hungarian Research Network, University of Szeged Danube Neuroscience Research Laboratory, Tisza Lajos krt. 113, H-6725 Szeged, Hungary"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,6,25]]},"reference":[{"key":"ref_1","first-page":"e58776","article-title":"From Alzheimer\u2019s Disease to Anxiety, Epilepsy to Schizophrenia: A Comprehensive Dive Into Neuro-Psychiatric Disorders","volume":"16","author":"Grezenko","year":"2024","journal-title":"Cureus"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"837","DOI":"10.1038\/s41386-018-0090-0","article-title":"Multivariate meta-analyses of mitochondrial complex I and IV in major depressive disorder, bipolar disorder, schizophrenia, Alzheimer disease, and Parkinson disease","volume":"44","author":"Holper","year":"2019","journal-title":"Neuropsychopharmacology"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"803","DOI":"10.1016\/j.molmed.2020.03.010","article-title":"Adult hippocampal neurogenesis in major depressive disorder and Alzheimer\u2019s disease","volume":"26","author":"Berger","year":"2020","journal-title":"Trends Mol. 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