{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,14]],"date-time":"2026-09-14T23:48:01Z","timestamp":1789429681120,"version":"build-2803163510"},"reference-count":31,"publisher":"MDPI AG","issue":"6","license":[{"start":{"date-parts":[[2021,3,12]],"date-time":"2021-03-12T00:00:00Z","timestamp":1615507200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100004281","name":"Narodowe Centrum Nauki","doi-asserted-by":"publisher","award":["2017\/25\/B\/NZ7\/01048"],"award-info":[{"award-number":["2017\/25\/B\/NZ7\/01048"]}],"id":[{"id":"10.13039\/501100004281","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100009045","name":"Uniwersytet Jagiello\u0144ski Collegium Medicum","doi-asserted-by":"publisher","award":["N42\/DBS\/000020, K\/DSC\/005295, No N42\/DBS\/000048"],"award-info":[{"award-number":["N42\/DBS\/000020, K\/DSC\/005295, No N42\/DBS\/000048"]}],"id":[{"id":"10.13039\/100009045","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Molecules"],"abstract":"<jats:p>The new series of 3-(2-chlorophenyl)- and 3-(3-chlorophenyl)-pyrrolidine-2,5-dione-acetamide derivatives as potential anticonvulsant and analgesic agents was synthesized. The compounds obtained were evaluated in the following acute models of epilepsy: maximal electroshock (MES), psychomotor (6 Hz, 32 mA), and subcutaneous pentylenetetrazole (scPTZ) seizure tests. The most active substance-3-(2-chlorophenyl)-1-{2-[4-(4-fluorophenyl)piperazin-1-yl]-2-oxoethyl}-pyrrolidine-2,5-dione (6) showed more beneficial ED50 and protective index values than the reference drug\u2014valproic acid (68.30 mg\/kg vs. 252.74 mg\/kg in the MES test and 28.20 mg\/kg vs. 130.64 mg\/kg in the 6 Hz (32 mA) test, respectively). Since anticonvulsant drugs are often effective in neuropathic pain management, the antinociceptive activity for two the promising compounds\u2014namely, 6 and 19\u2014was also investigated in the formalin model of tonic pain. Additionally, for the aforementioned compounds, the affinity for the voltage-gated sodium and calcium channels, as well as GABAA and TRPV1 receptors, was determined. As a result, the most probable molecular mechanism of action for the most active compound 6 relies on interaction with neuronal voltage-sensitive sodium (site 2) and L-type calcium channels. Compounds 6 and 19 were also tested for their neurotoxic and hepatotoxic properties and showed no significant cytotoxic effect.<\/jats:p>","DOI":"10.3390\/molecules26061564","type":"journal-article","created":{"date-parts":[[2021,3,14]],"date-time":"2021-03-14T23:52:06Z","timestamp":1615765926000},"page":"1564","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":17,"title":["Synthesis, Anticonvulsant, and Antinociceptive Activity of New 3-(2-Chlorophenyl)- and 3-(3-Chlorophenyl)-2,5-dioxo-pyrrolidin-1-yl-acetamides"],"prefix":"10.3390","volume":"26","author":[{"given":"Ma\u0142gorzata","family":"G\u00f3ra","sequence":"first","affiliation":[{"name":"Department of Medicinal Chemistry, Faculty of Pharmacy, Jagiellonian University Medical College, Medyczna 9 St., 30-688 Krakow, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1448-9826","authenticated-orcid":false,"given":"Anna","family":"Czopek","sequence":"additional","affiliation":[{"name":"Department of Medicinal Chemistry, Faculty of Pharmacy, Jagiellonian University Medical College, Medyczna 9 St., 30-688 Krakow, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0190-1682","authenticated-orcid":false,"given":"Anna","family":"Rapacz","sequence":"additional","affiliation":[{"name":"Department of Pharmacodynamics, Faculty of Pharmacy, Jagiellonian University Medical College, Medyczna 9 St., 30-688 Krakow, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anna","family":"G\u0119bska","sequence":"additional","affiliation":[{"name":"Department of Pharmacodynamics, Faculty of Pharmacy, Jagiellonian University Medical College, Medyczna 9 St., 30-688 Krakow, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2477-5607","authenticated-orcid":false,"given":"Katarzyna","family":"W\u00f3jcik-Pszczo\u0142a","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Biochemistry, Faculty of Pharmacy, Jagiellonian University Medical College, Medyczna 9 St., 30-688 Krakow, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1260-4253","authenticated-orcid":false,"given":"El\u017cbieta","family":"P\u0119kala","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Biochemistry, Faculty of Pharmacy, Jagiellonian University Medical College, Medyczna 9 St., 30-688 Krakow, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2103-371X","authenticated-orcid":false,"given":"Krzysztof","family":"Kami\u0144ski","sequence":"additional","affiliation":[{"name":"Department of Medicinal Chemistry, Faculty of Pharmacy, Jagiellonian University Medical College, Medyczna 9 St., 30-688 Krakow, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2021,3,12]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"522","DOI":"10.1111\/epi.13670","article-title":"Operational Classification of Seizure Types by the International League Against Epilepsy: Position Paper of the ILAE Commission for Classification and Terminology","volume":"58","author":"Fisher","year":"2017","journal-title":"Epilepsia"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1321","DOI":"10.1007\/s40265-018-0959-6","article-title":"Pharmacotherapy for Focal Seizures in Children and Adolescents","volume":"78","author":"Stevens","year":"2018","journal-title":"Drugs"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"279","DOI":"10.1001\/jamaneurol.2017.3949","article-title":"Treatment Outcomes in Patients With Newly Diagnosed Epilepsy Treated With Established and New Antiepileptic Drugs: A 30-Year Longitudinal Cohort Study","volume":"75","author":"Chen","year":"2018","journal-title":"JAMA Neurol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"107811","DOI":"10.1016\/j.neuropharm.2019.107811","article-title":"The Current Approach of the Epilepsy Therapy Screening Program Contract Site for Identifying Improved Therapies for the Treatment of Pharmacoresistant Seizures in Epilepsy","volume":"166","author":"Wilcox","year":"2020","journal-title":"Neuropharmacology"},{"key":"ref_5","first-page":"CD007076","article-title":"Pregabalin for Neuropathic Pain in Adults","volume":"1","author":"Derry","year":"2019","journal-title":"Cochrane Database Syst. Rev."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"239","DOI":"10.1016\/j.ejphar.2016.04.033","article-title":"Anticonvulsant and Antinociceptive Activity of New Amides Derived from 3-Phenyl-2,5-Dioxo-Pyrrolidine-1-Yl-Acetic Acid in Mice","volume":"781","author":"Rapacz","year":"2016","journal-title":"Eur. J. Pharmacol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"6149","DOI":"10.1016\/j.bmc.2011.08.017","article-title":"Synthesis and Anticonvulsant Activity of New N-Mannich Bases Derived from 5-Cyclopropyl-5-Phenyl- and 5-Cyclopropyl-5-(4-Chlorophenyl)-Imidazolidine-2,4-Diones","volume":"19","author":"Byrtus","year":"2011","journal-title":"Bioorg. Med. Chem."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"333","DOI":"10.1002\/ardp.200900250","article-title":"Synthesis and Anticonvulsant Properties of New Mannich Bases Derived from 3-Aryl-Pyrrolidine-2,5-Diones. Part 1","volume":"343","author":"Obniska","year":"2010","journal-title":"Archiv. Pharm."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"4895","DOI":"10.1021\/ja01154a126","article-title":"Anticonvulsants. I. An Investigation of N-R-a-R,-a-Phenylsuccinimides","volume":"73","author":"Miller","year":"1951","journal-title":"J. Am. Chem. Soc."},{"key":"ref_10","unstructured":"(2020, August 25). SwissAdme. Available online: http:\/\/www.swissadme.ch\/."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1016\/S0169-409X(00)00129-0","article-title":"Experimental and Computational Approaches to Estimate Solubility and Permeability in Drug Discovery and Development Settings1PII of Original Article: S0169-409X(96)00423-1. The Article Was Originally Published in Advanced Drug Delivery Reviews 23 (1997) 3\u201325.1","volume":"46","author":"Lipinski","year":"2001","journal-title":"Adv. Drug Deliv. Rev."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"2615","DOI":"10.1021\/jm020017n","article-title":"Molecular Properties That Influence the Oral Bioavailability of Drug Candidates","volume":"45","author":"Veber","year":"2002","journal-title":"J. Med. Chem."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"1115","DOI":"10.1016\/j.chembiol.2014.08.013","article-title":"Oral Druggable Space beyond the Rule of 5: Insights from Drugs and Clinical Candidates","volume":"21","author":"Doak","year":"2014","journal-title":"Chem. Biol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"5343","DOI":"10.1016\/j.bmc.2011.11.064","article-title":"Softening the Rule of Five\u2014Where to Draw the Line?","volume":"20","author":"Petit","year":"2012","journal-title":"Bioorg. Med. Chem."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"2548","DOI":"10.1016\/j.bmc.2015.03.038","article-title":"Design, Synthesis and Biological Evaluation of New Hybrid Anticonvulsants Derived from N-Benzyl-2-(2,5-Dioxopyrrolidin-1-Yl)Propanamide and 2-(2,5-Dioxopyrrolidin-1-Yl)Butanamide Derivatives","volume":"23","author":"Rapacz","year":"2015","journal-title":"Bioorg. Med. Chem"},{"key":"ref_16","first-page":"e10204","article-title":"Anti-Inflammatory and Antinociceptive Effects of the Isatin Derivative (Z)-2-(5-Chloro-2-Oxoindolin-3-Ylidene)-N-Phenyl-Hydrazinecarbothioamide in Mice","volume":"53","author":"Dantas","year":"2020","journal-title":"J. Med. Biol. Res."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"1168","DOI":"10.1124\/jpet.302.3.1168","article-title":"Comparison of Antiepileptic Drugs Tiagabine, Lamotrigine, and Gabapentin in Mouse Models of Acute, Prolonged, and Chronic Nociception","volume":"302","author":"Laughlin","year":"2002","journal-title":"J. Pharmacol. Exp. Ther."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"109753","DOI":"10.1016\/j.biopha.2019.109753","article-title":"Antipyretic, Anti-Inflammatory and Analgesic Activities of Periplaneta Americana Extract and Underlying Mechanisms","volume":"123","author":"Nguyen","year":"2020","journal-title":"Biomed. Pharm."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"235","DOI":"10.1016\/0304-3959(90)91167-H","article-title":"The Formalin Test in Mice: Effect of Formalin Concentration","volume":"42","author":"Rosland","year":"1990","journal-title":"Pain"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"17002","DOI":"10.1038\/nrdp.2017.2","article-title":"Neuropathic Pain","volume":"3","author":"Colloca","year":"2017","journal-title":"Nat. Rev. Dis. Primers"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"21","DOI":"10.1111\/j.1527-3458.2007.00001.x","article-title":"Lacosamide: A Review of Preclinical Properties","volume":"13","author":"Beyreuther","year":"2007","journal-title":"CNS Drug Rev."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"11","DOI":"10.1016\/j.eplepsyres.2018.03.024","article-title":"Evaluation of Anticonvulsant and Analgesic Activity of New Hybrid Compounds Derived from N-Phenyl-2-(2,5-Dioxopyrrolidin-1-Yl)-Propanamides and -Butanamides","volume":"143","author":"Rapacz","year":"2018","journal-title":"Epilepsy Res."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"39","DOI":"10.1016\/j.ejphar.2017.12.036","article-title":"Antiallodynic and Antihyperalgesic Activity of New 3,3-Diphenyl-Propionamides with Anticonvulsant Activity in Models of Pain in Mice","volume":"821","author":"Rapacz","year":"2018","journal-title":"Eur. J. Pharm."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"23","DOI":"10.1039\/C2TX20051A","article-title":"In Vitro Models for Liver Toxicity Testing","volume":"2","author":"Soldatow","year":"2013","journal-title":"Toxicol. Res."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"801","DOI":"10.1039\/C4TX00043A","article-title":"In Vitro Models for Neurotoxicology Research","volume":"4","author":"Barbosa","year":"2015","journal-title":"Toxicol. Res."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"171","DOI":"10.1016\/0920-1211(91)90062-K","article-title":"The Role of Technical, Biological and Pharmacological Factors in the Laboratory Evaluation of Anticonvulsant Drugs. III. Pentylenetetrazole Seizure Models","volume":"8","author":"Fassbender","year":"1991","journal-title":"Epilepsy Res."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"707","DOI":"10.1007\/s00702-014-1173-7","article-title":"Effects of WIN 55,212-2 (a Non-Selective Cannabinoid CB1 and CB 2 Receptor Agonist) on the Protective Action of Various Classical Antiepileptic Drugs in the Mouse 6 Hz Psychomotor Seizure Model","volume":"121","author":"Wlaz","year":"2014","journal-title":"J. Neural Transm."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"310","DOI":"10.1111\/epi.12893","article-title":"Genetic Background of Mice Strongly Influences Treatment Resistance in the 6 Hz Seizure Model","volume":"56","author":"Leclercq","year":"2015","journal-title":"Epilepsia"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/0920-1211(91)90041-D","article-title":"The Role of Technical, Biological and Pharmacological Factors in the Laboratory Evaluation of Anticonvulsant Drugs. IV. Protective Indices","volume":"9","author":"Nolting","year":"1991","journal-title":"Epilepsy Res."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"2064","DOI":"10.1523\/JNEUROSCI.06-07-02064.1986","article-title":"3H-Batrachotoxinin-A Benzoate Binding to Voltage-Sensitive Sodium Channels: Inhibition by the Channel Blockers Tetrodotoxin and Saxitoxin","volume":"6","author":"Brown","year":"1986","journal-title":"J. Neurosci."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"3656","DOI":"10.1073\/pnas.79.11.3656","article-title":"[3H]Nitrendipine-Labeled Calcium Channels Discriminate Inorganic Calcium Agonists and Antagonists","volume":"79","author":"Gould","year":"1982","journal-title":"Proc. Natl. Acad. Sci. USA"}],"container-title":["Molecules"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1420-3049\/26\/6\/1564\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T05:34:43Z","timestamp":1760160883000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1420-3049\/26\/6\/1564"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,3,12]]},"references-count":31,"journal-issue":{"issue":"6","published-online":{"date-parts":[[2021,3]]}},"alternative-id":["molecules26061564"],"URL":"https:\/\/doi.org\/10.3390\/molecules26061564","relation":{},"ISSN":["1420-3049"],"issn-type":[{"value":"1420-3049","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,3,12]]}}}