{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,19]],"date-time":"2026-06-19T17:43:14Z","timestamp":1781890994396,"version":"3.54.5"},"reference-count":67,"publisher":"MDPI AG","issue":"18","license":[{"start":{"date-parts":[[2024,9,11]],"date-time":"2024-09-11T00:00:00Z","timestamp":1726012800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Funda\u00e7\u00e3o de Amparo \u00e0 Pesquisa do Estado de Goi\u00e1s\u2014FAPEG","award":["202310267000252"],"award-info":[{"award-number":["202310267000252"]}]},{"name":"Funda\u00e7\u00e3o de Amparo \u00e0 Pesquisa do Estado de Goi\u00e1s\u2014FAPEG","award":["201810267001636"],"award-info":[{"award-number":["201810267001636"]}]},{"name":"Funda\u00e7\u00e3o de Amparo \u00e0 Pesquisa do Estado de Goi\u00e1s\u2014FAPEG","award":["2022151000060"],"award-info":[{"award-number":["2022151000060"]}]},{"name":"Funda\u00e7\u00e3o de Amparo \u00e0 Pesquisa do Estado de Goi\u00e1s\u2014FAPEG","award":["202310267001387"],"award-info":[{"award-number":["202310267001387"]}]},{"name":"Funda\u00e7\u00e3o de Amparo \u00e0 Pesquisa do Estado de Goi\u00e1s\u2014FAPEG","award":["315335\/2023-8"],"award-info":[{"award-number":["315335\/2023-8"]}]},{"name":"Funda\u00e7\u00e3o de Amparo \u00e0 Pesquisa do Estado de Goi\u00e1s\u2014FAPEG","award":["312130\/2019-8"],"award-info":[{"award-number":["312130\/2019-8"]}]},{"name":"Conselho Nacional de Desenvolvimento Cient\u00edfico e Tecnol\u00f3 gico\u2014CNPq","award":["202310267000252"],"award-info":[{"award-number":["202310267000252"]}]},{"name":"Conselho Nacional de Desenvolvimento Cient\u00edfico e Tecnol\u00f3 gico\u2014CNPq","award":["201810267001636"],"award-info":[{"award-number":["201810267001636"]}]},{"name":"Conselho Nacional de Desenvolvimento Cient\u00edfico e Tecnol\u00f3 gico\u2014CNPq","award":["2022151000060"],"award-info":[{"award-number":["2022151000060"]}]},{"name":"Conselho Nacional de Desenvolvimento Cient\u00edfico e Tecnol\u00f3 gico\u2014CNPq","award":["202310267001387"],"award-info":[{"award-number":["202310267001387"]}]},{"name":"Conselho Nacional de Desenvolvimento Cient\u00edfico e Tecnol\u00f3 gico\u2014CNPq","award":["315335\/2023-8"],"award-info":[{"award-number":["315335\/2023-8"]}]},{"name":"Conselho Nacional de Desenvolvimento Cient\u00edfico e Tecnol\u00f3 gico\u2014CNPq","award":["312130\/2019-8"],"award-info":[{"award-number":["312130\/2019-8"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>This work provides insight into carbamazepine polymorphs (Forms I, II, III, IV, and V), with reports on the cytoprotective, exploratory, motor, CNS-depressant, and anticonvulsant properties of carbamazepine (CBZ), carbamazepine formulation (CBZ-F), topiramate (TOP), oxcarbazepine (OXC), and diazepam (DZP) in mice. Structural analysis highlighted the significant difference in molecular conformations, which directly influence the physicochemical properties; and density functional theory description provided indications about CBZ reactivity and stability. In addition to neuron viability assessment in vitro, animals were treated orally with vehicle 10 mL\/kg, as well as CBZ, CBZ-F, TOP, OXC, and DZP at the dose of 5 mg\/kg and exposed to open-field, rotarod, barbiturate sleep induction and pentylenetetrazol (PTZ 70 mg\/kg)-induced seizure. The involvement of GABAergic mechanisms in the activity of these drugs was evaluated with the intraperitoneal pretreatment of flumazenil (2 mg\/kg). The CBZ, CBZ-F, and TOP mildly preserved neuronal viability. The CBZ-F and the reference AEDs potentiated barbiturate sleep, altered motor activities, and attenuated PTZ-induced convulsion. However, flumazenil pretreatment blocked these effects. Additional preclinical assessments could further establish the promising utility of CBZ-F in clinical settings while expanding the scope of AED formulations and designs.<\/jats:p>","DOI":"10.3390\/ijms25189835","type":"journal-article","created":{"date-parts":[[2024,9,11]],"date-time":"2024-09-11T10:33:01Z","timestamp":1726050781000},"page":"9835","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":15,"title":["Polymorphism and Pharmacological Assessment of Carbamazepine"],"prefix":"10.3390","volume":"25","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9434-4231","authenticated-orcid":false,"given":"Alberto","family":"S\u00e1 Filho","sequence":"first","affiliation":[{"name":"Graduate Program in Pharmaceutical Sciences, Evangelical University of Goi\u00e1s, Anapolis 75083-515, GO, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jose Luis Rodrigues","family":"Martins","sequence":"additional","affiliation":[{"name":"Graduate Program in Pharmaceutical Sciences, Evangelical University of Goi\u00e1s, Anapolis 75083-515, GO, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rafael Fernandes","family":"Costa","sequence":"additional","affiliation":[{"name":"Graduate Program in Pharmaceutical Sciences, Evangelical University of Goi\u00e1s, Anapolis 75083-515, GO, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0488-5400","authenticated-orcid":false,"given":"Gustavo Rodrigues","family":"Pedrino","sequence":"additional","affiliation":[{"name":"Institute of Biological Sciences, Federal University of Goi\u00e1s, Goi\u00e1s 74605-010, GO, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vitor Santos","family":"Duarte","sequence":"additional","affiliation":[{"name":"Structural and Theoretical Chemistry Group, State University of Goi\u00e1s, An\u00e1polis 75083-515, GO, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2148-131X","authenticated-orcid":false,"given":"Osmar Nascimento","family":"Silva","sequence":"additional","affiliation":[{"name":"Graduate Program in Pharmaceutical Sciences, Evangelical University of Goi\u00e1s, Anapolis 75083-515, GO, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6047-9995","authenticated-orcid":false,"given":"Hamilton Barbosa","family":"Napolitano","sequence":"additional","affiliation":[{"name":"Graduate Program in Pharmaceutical Sciences, Evangelical University of Goi\u00e1s, Anapolis 75083-515, GO, Brazil"},{"name":"Structural and Theoretical Chemistry Group, State University of Goi\u00e1s, An\u00e1polis 75083-515, GO, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7440-7581","authenticated-orcid":false,"given":"James Oluwagbamigbe","family":"Fajemiroye","sequence":"additional","affiliation":[{"name":"Graduate Program in Pharmaceutical Sciences, Evangelical University of Goi\u00e1s, Anapolis 75083-515, GO, Brazil"},{"name":"Institute of Biological Sciences, Federal University of Goi\u00e1s, Goi\u00e1s 74605-010, GO, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2024,9,11]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"935","DOI":"10.1007\/s40263-021-00827-8","article-title":"The pharmacology and clinical efficacy of antiseizure medications: From bromide salts to cenobamate and beyond","volume":"35","author":"Klein","year":"2021","journal-title":"CNS Drugs"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"512","DOI":"10.1111\/epi.13709","article-title":"ILAE classification of the epilepsies: Position paper of the ILAE Commission for Classification and Terminology","volume":"58","author":"Scheffer","year":"2017","journal-title":"Epilepsia"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1000","DOI":"10.1016\/S0140-6736(07)60460-7","article-title":"The SANAD study of effectiveness of carbamazepine, gabapentin, lamotrigine, oxcarbazepine, or topiramate for treatment of partial epilepsy: An unblinded randomised controlled trial","volume":"369","author":"Marson","year":"2007","journal-title":"Lancet"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"115108","DOI":"10.1016\/j.addr.2023.115108","article-title":"Revolutionizing drug formulation development: The increasing impact of machine learning","volume":"202","author":"Bao","year":"2023","journal-title":"Adv. Drug Deliv. Rev."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"40","DOI":"10.1021\/mp800128y","article-title":"Justification of biowaiver for carbamazepine, a low soluble high permeable compound, in solid dosage forms based on IVIVC and gastrointestinal simulation","volume":"6","author":"Kovacevic","year":"2009","journal-title":"Mol. Pharm."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"1935","DOI":"10.1016\/j.xphs.2021.02.019","article-title":"Biowaiver monograph for immediate-release solid oral dosage forms: Carbamazepine","volume":"110","author":"Cristofoletti","year":"2021","journal-title":"J. Pharm. Sci."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"413","DOI":"10.1023\/A:1016212804288","article-title":"A theoretical basis for a biopharmaceutic drug classification: The correlation of in vitro drug product dissolution and in vivo bioavailability","volume":"12","author":"Amidon","year":"1995","journal-title":"Pharm. Res."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"41","DOI":"10.1016\/S0731-7085(00)00262-4","article-title":"Solid-state study of polymorphic drugs: Carbamazepine","volume":"23","author":"Rustichelli","year":"2000","journal-title":"J. Pharm. Biomed. Anal."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"3755","DOI":"10.1021\/acs.cgd.9b00154","article-title":"Controlling polymorphism of carbamazepine nanoparticles in a continuous supercritical-CO2-assisted spray drying process","volume":"19","author":"Long","year":"2019","journal-title":"Cryst. Growth Des."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"2260","DOI":"10.1002\/jps.10455","article-title":"Comparison of the four anhydrous polymorphs of carbamazepine and the crystal structure of form I","volume":"92","author":"Grzesiak","year":"2003","journal-title":"J. Pharm. Sci."},{"key":"ref_11","doi-asserted-by":"crossref","unstructured":"Saifee, M., Inamda, N., Dhamecha, D., and Rathi, A. (2009). Drug polymorphism: A review. Int. J. Health Res., 2.","DOI":"10.4314\/ijhr.v2i4.55423"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"118","DOI":"10.1016\/S1461-5347(98)00031-5","article-title":"Physical characterization of polymorphic drugs: An integrated characterization strategy","volume":"1","author":"Yu","year":"1998","journal-title":"Pharm. Sci. Technol. Today"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"464","DOI":"10.1002\/jps.22788","article-title":"Polymorphism and solvatomorphism 2010","volume":"101","author":"Brittain","year":"2012","journal-title":"J. Pharm. Sci."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"699","DOI":"10.1081\/DDC-100107327","article-title":"Modification of crystal habit and its role in dosage form performance","volume":"27","author":"Tiwary","year":"2001","journal-title":"Drug Dev. Ind. Pharm."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"18759","DOI":"10.3390\/molecules201018759","article-title":"Polymorph Impact on the Bioavailability and Stability of Poorly Soluble Drugs","volume":"20","author":"Censi","year":"2015","journal-title":"Molecules"},{"key":"ref_16","doi-asserted-by":"crossref","unstructured":"Reig-L\u00f3pez, J., Cuquerella-Gilabert, M., Band\u00edn-Vilar, E., Merino-Sanju\u00e1n, M., Mangas-Sanju\u00e1n, V., and Garc\u00eda-Arieta, A. (2024). Bioequivalence risk assessment of oral formulations containing racemic ibuprofen through a chiral physiologically based pharmacokinetic model of ibuprofen enantiomers. Eur. J. Pharm. Biopharm., 17.","DOI":"10.1016\/j.ejpb.2024.114293"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"79","DOI":"10.1016\/j.ejps.2019.03.012","article-title":"Combining amorphous solid dispersions for improved kinetic solubility of posaconazole simultaneously released from soluble PVP\/VA64 and an insoluble ammonio methacrylate copolymer","volume":"133","author":"Danda","year":"2019","journal-title":"Eur. J. Pharm. Sci."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"118828","DOI":"10.1016\/j.ijpharm.2019.118828","article-title":"Metronidazole\/Hydroxypropyl-beta-Cyclodextrin inclusion complex nanofibrous webs as fast-dissolving oral drug delivery system","volume":"572","author":"Celebioglu","year":"2019","journal-title":"Int. J. Pharm."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"99","DOI":"10.1016\/j.biochi.2016.07.008","article-title":"Nano-formulations of drugs: Recent developments, impact and challenges","volume":"128","author":"Jeevanandam","year":"2016","journal-title":"Biochimie"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"655","DOI":"10.1111\/j.1528-1157.1980.tb04319.x","article-title":"Single-drug therapy with carbamazepine in patients with epilepsy: Serum levels and clinical effect","volume":"21","author":"Strandjord","year":"1980","journal-title":"Epilepsia"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"146","DOI":"10.4161\/chan.24380","article-title":"Voltage-gated sodium channels: Pharmaceutical targets via anticonvulsants to treat epileptic syndromes","volume":"7","author":"Abdelsayed","year":"2013","journal-title":"Channels"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"1296","DOI":"10.1152\/jn.00232.2012","article-title":"Seizures as imbalanced up states: Excitatory and inhibitory conductances during seizure-like events","volume":"109","author":"Cressman","year":"2013","journal-title":"J. Neurophysiol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"107966","DOI":"10.1016\/j.neuropharm.2020.107966","article-title":"Mechanisms of action of currently used antiseizure drugs","volume":"168","author":"Sills","year":"2020","journal-title":"Neuropharmacology"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"66","DOI":"10.1107\/S2056989020016163","article-title":"Crystal structure of 2-hy-droxy-2-phenyl-aceto-phenone oxime","volume":"77","author":"Akduran","year":"2021","journal-title":"Acta Crystallogr. E Crystallogr. Commun."},{"key":"ref_25","doi-asserted-by":"crossref","unstructured":"van der Merwe, J., Steenekamp, J., Steyn, D., and Hamman, J. (2020). The Role of Functional Excipients in Solid Oral Dosage Forms to Overcome Poor Drug Dissolution and Bioavailability. Pharmaceutics, 12.","DOI":"10.3390\/pharmaceutics12050393"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"120","DOI":"10.1007\/BF02975147","article-title":"Surfactant effects upon dissolution patterns of carbamazepine immediate release tablet","volume":"28","author":"Lee","year":"2005","journal-title":"Arch. Pharm. Res."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"893","DOI":"10.1080\/03639040600762677","article-title":"Towards a universal dissolution medium for carbamazepine","volume":"32","author":"Abdallah","year":"2006","journal-title":"Drug Dev. Ind. Pharm."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"797","DOI":"10.1023\/A:1023493821302","article-title":"Dissolution behavior of a poorly water soluble compound in the presence of Tween 80","volume":"20","author":"Chert","year":"2003","journal-title":"Pharm. Res."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"384","DOI":"10.1021\/js960105t","article-title":"Dissolution media for in vitro testing of water-insoluble drugs: Effect of surfactant purity and electrolyte on in vitro dissolution of carbamazepine in aqueous solutions of sodium lauryl sulfate","volume":"86","author":"Crison","year":"1997","journal-title":"J. Pharm. Sci."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"689","DOI":"10.1126\/science.7901908","article-title":"Oxidative stress, glutamate, and neurodegenerative disorders","volume":"262","author":"Coyle","year":"1993","journal-title":"Science"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"209","DOI":"10.1016\/j.bjp.2015.09.011","article-title":"Neuropharmacological effects of the ethanolic extract of Sida acuta","volume":"26","author":"Benjumea","year":"2016","journal-title":"Rev. Bras. Farmacogn."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"597","DOI":"10.1007\/BF02244990","article-title":"The stimulant effect of modafinil on wakefulness is not associated with an increase in anxiety in mice. A comparison with dexamphetamine","volume":"114","author":"Simon","year":"1994","journal-title":"Psychopharmacology"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"115","DOI":"10.1590\/S0102-695X2011005000018","article-title":"Anxiolytic-like and sedative effects of Hydrocotyle umbellata L., Araliaceae, extract in mice","volume":"21","author":"Rocha","year":"2011","journal-title":"Rev. Bras. Farmacogn."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"872","DOI":"10.1016\/j.jep.2012.03.043","article-title":"Involvement of 5-HT1A in the anxiolytic-like effect of dichloromethane fraction of Pimenta pseudocaryophyllus","volume":"141","author":"Fajemiroye","year":"2012","journal-title":"J. Ethnopharmacol."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"21","DOI":"10.1016\/S0163-7258(01)00122-X","article-title":"The mechanisms of action of commonly used antiepileptic drugs","volume":"90","author":"Kwan","year":"2001","journal-title":"Pharmacol. Ther."},{"key":"ref_36","doi-asserted-by":"crossref","unstructured":"Thapliyal, S., and Babu, K. (2018). Pentylenetetrazole (PTZ)-induced Convulsion Assay to Determine GABAergic Defects in Caenorhabditis elegans. Bio Protoc., 8.","DOI":"10.21769\/BioProtoc.2989"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"167","DOI":"10.1016\/S0920-1211(97)00045-4","article-title":"Topiramate enhances GABA-mediated chloride flux and GABA-evoked chloride currents in murine brain neurons and increases seizure threshold","volume":"28","author":"White","year":"1997","journal-title":"Epilepsy Res."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"744","DOI":"10.1002\/jps.2600760914","article-title":"Physicochemical properties and X-ray structural studies of the trigonal polymorph of carbamazepine","volume":"76","author":"Lowes","year":"1987","journal-title":"J. Pharm. Sci."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"213","DOI":"10.1107\/S0021889810042561","article-title":"Evaluation of the Bruker SMART X2S: Crystallography for the nonspecialist?","volume":"44","author":"Eccles","year":"2011","journal-title":"J. Appl. Crystallogr."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"1186","DOI":"10.1002\/jps.10093","article-title":"Form IV of carbamazepine","volume":"91","author":"Lang","year":"2002","journal-title":"J. Pharm. Sci."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"7074","DOI":"10.1039\/c1cc11634g","article-title":"A strategy for producing predicted polymorphs: Catemeric carbamazepine form V","volume":"47","author":"Arlin","year":"2011","journal-title":"Chem. Commun."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"453","DOI":"10.1107\/S002188980600731X","article-title":"Mercury: Visualization and analysis of crystal structures","volume":"39","author":"Macrae","year":"2006","journal-title":"J. Appl. Crystallogr."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"339","DOI":"10.1107\/S0021889808042726","article-title":"OLEX2: A complete structure solution, refinement and analysis program","volume":"42","author":"Dolomanov","year":"2009","journal-title":"J. Appl. Crystallogr."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"627","DOI":"10.1107\/S0108768104020300","article-title":"Novel tools for visualizing and exploring intermolecular interactions in molecular crystals","volume":"60","author":"McKinnon","year":"2004","journal-title":"Acta Crystallogr. B"},{"key":"ref_45","doi-asserted-by":"crossref","unstructured":"McKinnon, J.J., Jayatilaka, D., and Spackman, M.A. (2007). Towards quantitative analysis of intermolecular interactions with Hirshfeld surfaces. Chem. Commun., 3814\u20133816.","DOI":"10.1039\/b704980c"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"19","DOI":"10.1039\/B818330A","article-title":"Hirshfeld surface analysis","volume":"11","author":"Spackman","year":"2009","journal-title":"CrystEngComm"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"378","DOI":"10.1039\/B203191B","article-title":"Fingerprinting intermolecular interactions in molecular crystals","volume":"4","author":"Spackman","year":"2002","journal-title":"CrystEngComm"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"150901","DOI":"10.1063\/1.4704546","article-title":"Perspective on density functional theory","volume":"136","author":"Burke","year":"2012","journal-title":"J. Chem. Phys."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"215","DOI":"10.1007\/s00214-007-0310-x","article-title":"The M06 suite of density functionals for main group thermochemistry, thermochemical kinetics, noncovalent interactions, excited states, and transition elements: Two new functionals and systematic testing of four M06-class functionals and 12 other functionals","volume":"120","author":"Zhao","year":"2008","journal-title":"Theor. Chem. Acc."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"650","DOI":"10.1063\/1.438955","article-title":"Self-consistent molecular orbital methods. XX. A basis set for correlated wave functions","volume":"72","author":"Krishnan","year":"1980","journal-title":"J. Chem. Phys."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"5639","DOI":"10.1063\/1.438980","article-title":"Contracted Gaussian basis sets for molecular calculations. I. Second row atoms, Z= 11\u201318","volume":"72","author":"McLean","year":"1980","journal-title":"J. Chem. Phys."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"1996","DOI":"10.1021\/ct800308k","article-title":"Assessment of the Performance of the M05-2X and M06-2X Exchange-Correlation Functionals for Noncovalent Interactions in Biomolecules","volume":"4","author":"Hohenstein","year":"2008","journal-title":"J. Chem. Theory Comput."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"1342","DOI":"10.1002\/jcc.20058","article-title":"Basis set effects on calculated geometries: 6-311++G** vs. aug-cc-pVDZ","volume":"25","author":"Wiberg","year":"2004","journal-title":"J. Comput. Chem."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"10439","DOI":"10.1021\/jp0734474","article-title":"General performance of density functionals","volume":"111","author":"Sousa","year":"2007","journal-title":"J. Phys. Chem. A"},{"key":"ref_55","doi-asserted-by":"crossref","unstructured":"Pereira, D.H., La Porta, F., Santiago, R., Garcia, D., and Ramalho, T. (2016). New perspectives on the role of frontier molecular orbitals in the study of chemical reactivity: A review. Rev. Virtual Quimica, 425\u2013453.","DOI":"10.5935\/1984-6835.20160032"},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"153","DOI":"10.1002\/wcms.19","article-title":"The electrostatic potential: An overview","volume":"1","author":"Murray","year":"2011","journal-title":"Wiley Interdiscip. Rev. Comput. Mol. Sci."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"3754","DOI":"10.1073\/pnas.79.12.3754","article-title":"Electrostatic potential molecular surfaces","volume":"79","author":"Weiner","year":"1982","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"2957","DOI":"10.1007\/s00210-023-02502-9","article-title":"Preclinical data on morpholine (3,5-di-tertbutyl-4-hydroxyphenyl) methanone induced anxiolysis","volume":"396","author":"Cabral","year":"2023","journal-title":"Naunyn Schmiedebergs Arch. Pharmacol."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"923","DOI":"10.1177\/0269881114536789","article-title":"Plurality of anxiety and depression alteration mechanism by oleanolic acid","volume":"28","author":"Fajemiroye","year":"2014","journal-title":"J. Psychopharmacol."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"432","DOI":"10.1111\/cbdd.12961","article-title":"Anxiolytic-like effect of 2-(4-((1-phenyl-1H-pyrazol-4-yl)methyl)piperazin-1-yl)ethan-1-ol is mediated through the benzodiazepine and nicotinic pathways","volume":"90","author":"Brito","year":"2017","journal-title":"Chem. Biol. Drug Des."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"1819","DOI":"10.1039\/C4FO00109E","article-title":"Anxiolytic and antidepressant like effects of natural food flavour (E)-methyl isoeugenol","volume":"5","author":"Fajemiroye","year":"2014","journal-title":"Food Funct."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"180","DOI":"10.1016\/j.jneumeth.2010.03.026","article-title":"A rotarod test for evaluation of motor skill learning","volume":"189","author":"Shiotsuki","year":"2010","journal-title":"J. Neurosci. Methods"},{"key":"ref_63","doi-asserted-by":"crossref","unstructured":"Shi, X., Bai, H., Wang, J., Wang, J., Huang, L., He, M., Zheng, X., Duan, Z., Chen, D., and Zhang, J. (2021). Behavioral Assessment of Sensory, Motor, Emotion, and Cognition in Rodent Models of Intracerebral Hemorrhage. Front. Neurol., 12.","DOI":"10.3389\/fneur.2021.667511"},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"910","DOI":"10.1016\/j.lfs.2012.04.037","article-title":"Central pharmacological activity of a new piperazine derivative: 4-(1-Phenyl-1h-pyrazol-4-ylmethyl)-piperazine-1-carboxylic acid ethyl ester","volume":"90","author":"Fajemiroye","year":"2012","journal-title":"J. Life Sci."},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"211","DOI":"10.1007\/BF00537801","article-title":"A rotarod suitable for quantitative measurements of motor incoordination in naive mice","volume":"259","author":"Jones","year":"1968","journal-title":"Naunyn Schmiedebergs Arch. Exp. Pathol. Pharmakol."},{"key":"ref_66","first-page":"25","article-title":"Screening farmacol\u00f3gico de ansiol\u00edticos: Metodologia laboratorial e compara\u00e7\u00e3o entre o diazepam e o clorobenzapam","volume":"1","author":"Carlini","year":"1979","journal-title":"Rev. Bras. Psiquiatr."},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"165","DOI":"10.1080\/1028415X.2017.1357919","article-title":"Anticonvulsant effects of thiamine on pentylenetetrazole-induced seizure in mice","volume":"22","author":"Mesdaghinia","year":"2019","journal-title":"Nutr. Neurosci."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/25\/18\/9835\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T15:54:04Z","timestamp":1760111644000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/25\/18\/9835"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,9,11]]},"references-count":67,"journal-issue":{"issue":"18","published-online":{"date-parts":[[2024,9]]}},"alternative-id":["ijms25189835"],"URL":"https:\/\/doi.org\/10.3390\/ijms25189835","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,9,11]]}}}