{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,3]],"date-time":"2026-09-03T05:16:40Z","timestamp":1788412600820,"version":"build-2803163510"},"reference-count":52,"publisher":"MDPI AG","issue":"17","license":[{"start":{"date-parts":[[2026,8,28]],"date-time":"2026-08-28T00:00:00Z","timestamp":1787875200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100003443","name":"The Ministry of Education and Science of the Russian Federation","doi-asserted-by":"crossref","award":["075-15-2024-548"],"award-info":[{"award-number":["075-15-2024-548"]}],"id":[{"id":"10.13039\/501100003443","id-type":"DOI","asserted-by":"crossref"}]},{"award":["075-15-2024-548"],"award-info":[{"award-number":["075-15-2024-548"]}],"id":[{"id":"https:\/\/ror.org\/00ghqgy32","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Int. J. Mol. Sci.","IJMS"],"abstract":"<jats:p>The development of antiepileptic drugs remains a serious challenge for both academia and industry. Ionotropic glutamate receptors and voltage-gated sodium channels are among the primary targets of antiepileptic agents. Recent studies have revealed a unique property of phenytoin: unlike other sodium-channel blockers, it inhibits calcium-impermeable AMPA receptors at micromolar concentrations. In this study, we explored the structure\u2013activity relationships of eight phenytoin derivatives. The effects of the compounds on neuronal voltage-gated Na+ channels and neuronal AMPA receptor channels were examined using the patch-clamp technique. For the Na+ channels, we analyzed tonic block, shifts of steady-state inactivation, and frequency-dependent block. For the AMPA receptors, we investigated kinetics, agonist dependence, and trapping effects. NH groups at positions 1 and 3, the carbonyl groups at positions 2 and 4, and the phenyl group at position 5 are important, since their replacement causes a decrease in activity. Replacement of oxygen with sulfur at position 2 results in a significant increase in activity on both types of channels. For the AMPA receptor, this increase is attributable to a more stable drug\u2013channel complex. The enhanced action on sodium channels is due to an increase in tonic block, whereas the effects on inactivated and open channels remain unchanged. These results suggest a new possibility for tuning the activities of phenytoin derivatives against both primary targets to obtain anticonvulsants with novel properties.<\/jats:p>","DOI":"10.3390\/ijms27177723","type":"journal-article","created":{"date-parts":[[2026,9,1]],"date-time":"2026-09-01T09:48:36Z","timestamp":1788256116000},"page":"7723","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Phenytoin Derivatives as Antagonists of AMPA Receptors and Voltage-Gated Sodium Channels: A Structure\u2013Function Study"],"prefix":"10.3390","volume":"27","author":[{"given":"Arseniy S.","family":"Zhigulin","sequence":"first","affiliation":[{"name":"Sechenov Institute of Evolutionary Physiology and Biochemistry, Russian Academy of Sciences, 194223 Saint Petersburg, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maxim V.","family":"Nikolaev","sequence":"additional","affiliation":[{"name":"Sechenov Institute of Evolutionary Physiology and Biochemistry, Russian Academy of Sciences, 194223 Saint Petersburg, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mikhail Y.","family":"Dron","sequence":"additional","affiliation":[{"name":"Sechenov Institute of Evolutionary Physiology and Biochemistry, Russian Academy of Sciences, 194223 Saint Petersburg, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dmitry A.","family":"Vasilenko","sequence":"additional","affiliation":[{"name":"Department of Chemistry, Lomonosov Moscow State University, 119991 Moscow, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4197-3277","authenticated-orcid":false,"given":"Oleg I.","family":"Barygin","sequence":"additional","affiliation":[{"name":"Sechenov Institute of Evolutionary Physiology and Biochemistry, Russian Academy of Sciences, 194223 Saint Petersburg, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8523-4305","authenticated-orcid":false,"given":"Denis B.","family":"Tikhonov","sequence":"additional","affiliation":[{"name":"Sechenov Institute of Evolutionary Physiology and Biochemistry, Russian Academy of Sciences, 194223 Saint Petersburg, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,8,28]]},"reference":[{"key":"ref_1","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_2","doi-asserted-by":"crossref","first-page":"114","DOI":"10.1002\/epi4.12268","article-title":"Brief history of anti-seizure drug development","volume":"3","author":"Rho","year":"2018","journal-title":"Epilepsia Open"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"106452","DOI":"10.1016\/j.eplepsyres.2020.106452","article-title":"Inhibitory effect of anti-seizure medications on ionotropic glutamate receptors: Special focus on AMPA receptor subunits","volume":"167","author":"Fukushima","year":"2020","journal-title":"Epilepsy Res."},{"key":"ref_4","doi-asserted-by":"crossref","unstructured":"Chen, C.Y., Matt, L., Hell, J.W., and Rogawski, M.A. (2014). Perampanel inhibition of AMPA receptor currents in cultured hippocampal neurons. PLoS ONE, 9.","DOI":"10.1371\/journal.pone.0108021"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1331","DOI":"10.1111\/j.1528-1167.2011.03109.x","article-title":"Perampanel: A novel, orally active, noncompetitive AMPA-receptor antagonist that reduces seizure activity in rodent models of epilepsy","volume":"52","author":"Hanada","year":"2011","journal-title":"Epilepsia"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"378","DOI":"10.1111\/ane.12879","article-title":"Perampanel, an AMPA receptor antagonist: From clinical research to practice in clinical settings","volume":"137","author":"Tsai","year":"2018","journal-title":"Acta Neurol. Scand."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"146","DOI":"10.1016\/j.neulet.2016.09.028","article-title":"Inhibition of calcium-permeable and calcium-impermeable AMPA receptors by perampanel in rat brain neurons","volume":"633","author":"Barygin","year":"2016","journal-title":"Neurosci. Lett."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"144","DOI":"10.1016\/j.neuropharm.2005.02.007","article-title":"Design of antagonists for NMDA and AMPA receptors","volume":"49","author":"Bolshakov","year":"2005","journal-title":"Neuropharmacology"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"298","DOI":"10.1124\/pharmrev.120.000131","article-title":"Structure, Function, and Pharmacology of Glutamate Receptor Ion Channels","volume":"73","author":"Hansen","year":"2021","journal-title":"Pharmacol. Rev."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"449","DOI":"10.1517\/17460441.2014.891580","article-title":"The discovery and development of perampanel for the treatment of epilepsy","volume":"9","author":"Hanada","year":"2014","journal-title":"Expert Opin. Drug Discov."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"R3","DOI":"10.1016\/0922-4106(94)90161-9","article-title":"Sensitivity of AMPA receptors to pentobarbital","volume":"267","author":"Taverna","year":"1994","journal-title":"Eur. J. Pharmacol. Mol. Pharmacol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"412","DOI":"10.1016\/0014-5793(95)01163-9","article-title":"The sensitivity of AMPA-selective glutamate receptor channels to pentobarbital is determined by a single amino acid residue of the alpha 2 subunit","volume":"374","author":"Yamakura","year":"1995","journal-title":"FEBS Lett."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"395","DOI":"10.1124\/mol.64.2.395","article-title":"Desensitization of alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors facilitates use-dependent inhibition by pentobarbital","volume":"64","author":"Jackson","year":"2003","journal-title":"Mol. Pharmacol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"74","DOI":"10.1093\/bja\/82.1.74","article-title":"Distinct molecular sites of anaesthetic action: Pentobarbital block of human brain sodium channels is alleviated by removal of fast inactivation","volume":"82","author":"Wartenberg","year":"1999","journal-title":"Br. J. Anaesth."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"211","DOI":"10.1016\/0169-328X(89)90056-9","article-title":"Pentobarbital suppresses human brain sodium channels","volume":"6","author":"Frenkel","year":"1989","journal-title":"Mol. Brain Res."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"640","DOI":"10.1097\/00000542-199004000-00012","article-title":"Molecular actions of pentobarbital isomers on sodium channels from human brain cortex","volume":"72","author":"Frenkel","year":"1990","journal-title":"Anesthesiology"},{"key":"ref_17","doi-asserted-by":"crossref","unstructured":"Dron, M.Y., Zhigulin, A.S., Tikhonov, D.B., and Barygin, O.I. (2021). Screening for Activity Against AMPA Receptors Among Anticonvulsants-Focus on Phenytoin. Front. Pharmacol., 12.","DOI":"10.3389\/fphar.2021.775040"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"716","DOI":"10.1016\/S0026-895X(25)09804-9","article-title":"Slow binding of phenytoin to inactivated sodium channels in rat hippocampal neurons","volume":"46","author":"Kuo","year":"1994","journal-title":"Mol. Pharmacol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"1044","DOI":"10.1016\/j.neuropharm.2006.11.001","article-title":"A pharmacophore derived phenytoin analogue with increased affinity for slow inactivated sodium channels exhibits a desired anticonvulsant profile","volume":"52","author":"Lenkowski","year":"2007","journal-title":"Neuropharmacology"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"111393","DOI":"10.1016\/j.fct.2020.111393","article-title":"Phenytoin\u2014An anti-seizure drug: Overview of its chemistry, pharmacology and toxicology","volume":"142","author":"Patocka","year":"2020","journal-title":"Food Chem. Toxicol. Int. J. Publ. Br. Ind. Biol. Res. Assoc."},{"key":"ref_21","doi-asserted-by":"crossref","unstructured":"Loscher, W. (2021). Single-Target Versus Multi-Target Drugs Versus Combinations of Drugs With Multiple Targets: Preclinical and Clinical Evidence for the Treatment or Prevention of Epilepsy. Front. Pharmacol., 12.","DOI":"10.3389\/fphar.2021.730257"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1124\/jpet.119.261149","article-title":"Pharmacological Profile of the Novel Antiepileptic Drug Candidate Padsevonil: Interactions with Synaptic Vesicle 2 Proteins and the GABA(A) Receptor","volume":"372","author":"Wood","year":"2020","journal-title":"J. Pharmacol. Exp. Ther."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"647","DOI":"10.1111\/epi.12950","article-title":"The anticonvulsant retigabine is a subtype selective modulator of GABAA receptors","volume":"56","author":"Treven","year":"2015","journal-title":"Epilepsia"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"98","DOI":"10.1016\/j.bpc.2013.12.003","article-title":"Molecular dynamics simulation of the partitioning of benzocaine and phenytoin into a lipid bilayer","volume":"185","author":"Martin","year":"2014","journal-title":"Biophys. Chem."},{"key":"ref_25","doi-asserted-by":"crossref","unstructured":"de Groot, B.L., Martin, L.J., and Corry, B. (2014). Locating the Route of Entry and Binding Sites of Benzocaine and Phenytoin in a Bacterial Voltage Gated Sodium Channel. PLoS Comput. Biol., 10.","DOI":"10.1371\/journal.pcbi.1003688"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"497","DOI":"10.1085\/jgp.69.4.497","article-title":"Local anesthetics: Hydrophilic and hydrophobic pathways for the drug-receptor reaction","volume":"69","author":"Hille","year":"1977","journal-title":"J. Gen. Physiol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"635","DOI":"10.1016\/j.ejps.2004.01.004","article-title":"Block of human NaV1.5 sodium channels by novel alpha-hydroxyphenylamide analogues of phenytoin","volume":"21","author":"Lenkowski","year":"2004","journal-title":"Eur. J. Pharm. Sci."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"655","DOI":"10.1111\/j.1469-7793.1997.655ba.x","article-title":"Block of open channels of recombinant AMPA receptors and native AMPA\/kainate receptors by adamantane derivatives","volume":"505","author":"Magazanik","year":"1997","journal-title":"J. Physiol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"81","DOI":"10.1016\/S0304-3940(99)00176-7","article-title":"Sodium channels (from rat, mouse, and man) in neuroblastoma cells and different expression systems have similar sensitivities to pentobarbital","volume":"264","author":"Rehberg","year":"1999","journal-title":"Neurosci. Lett."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"956","DOI":"10.1016\/j.neuron.2018.07.027","article-title":"Mechanisms of Channel Block in Calcium-Permeable AMPA Receptors","volume":"99","author":"Twomey","year":"2018","journal-title":"Neuron"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"160","DOI":"10.1038\/nrd1958","article-title":"Paradigm shift in neuroprotection by NMDA receptor blockade: Memantine and beyond","volume":"5","author":"Lipton","year":"2006","journal-title":"Nat. Rev. Drug Discov."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"237","DOI":"10.1021\/acsmedchemlett.8b00322","article-title":"Modulation of AMPA Receptor Gating by the Anticonvulsant Drug, Perampanel","volume":"10","author":"Yuan","year":"2019","journal-title":"ACS Med. Chem. Lett."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"1305","DOI":"10.1016\/j.neuron.2016.08.012","article-title":"Structural Bases of Noncompetitive Inhibition of AMPA-Subtype Ionotropic Glutamate Receptors by Antiepileptic Drugs","volume":"91","author":"Yelshanskaya","year":"2016","journal-title":"Neuron"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"869","DOI":"10.1111\/ejn.12817","article-title":"Non-classical mechanism of alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor channel block by fluoxetine","volume":"41","author":"Barygin","year":"2015","journal-title":"Eur. J. Neurosci."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"4114","DOI":"10.1038\/s41467-022-31817-z","article-title":"Inhibition of NMDA receptors through a membrane-to-channel path","volume":"13","author":"Wilcox","year":"2022","journal-title":"Nat. Commun."},{"key":"ref_36","first-page":"e2752","article-title":"Vibrodissociation of neurons from rodent brain slices to study synaptic transmission and image presynaptic terminals","volume":"51","author":"Jun","year":"2011","journal-title":"J. Vis. Exp. JoVE"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"145","DOI":"10.1016\/0165-0270(91)90164-U","article-title":"Vibrodissociation of sliced mammalian nervous tissue","volume":"38","author":"Vorobjev","year":"1991","journal-title":"J. Neurosci. Methods"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"819","DOI":"10.1523\/JNEUROSCI.17-02-00819.1997","article-title":"Cellular, subcellular, and subsynaptic distribution of AMPA-type glutamate receptor subunits in the neostriatum of the rat","volume":"17","author":"Bernard","year":"1997","journal-title":"J. Neurosci. Off. J. Soc. Neurosci."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"204","DOI":"10.1523\/JNEUROSCI.17-01-00204.1997","article-title":"Functional properties of AMPA and NMDA receptors expressed in identified types of basal ganglia neurons","volume":"17","author":"Gotz","year":"1997","journal-title":"J. Neurosci. Off. J. Soc. Neurosci."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"8213","DOI":"10.1021\/bi200617v","article-title":"Argiotoxin in the closed AMPA receptor channel: Experimental and modeling study","volume":"50","author":"Barygin","year":"2011","journal-title":"Biochemistry"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"52","DOI":"10.1016\/S0006-8993(99)01970-8","article-title":"Characterization of AMPA receptor populations in rat brain cells by the use of subunit-specific open channel blocking drug, IEM-1460","volume":"846","author":"Buldakova","year":"1999","journal-title":"Brain Res."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"261","DOI":"10.1016\/S0306-4522(99)00326-7","article-title":"The open channel blocking drug, IEM-1460, reveals functionally distinct alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionate receptors in rat brain neurons","volume":"94","author":"Samoilova","year":"1999","journal-title":"Neuroscience"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"112988","DOI":"10.1016\/j.inoche.2024.112988","article-title":"Magnetic chitosan-benzoin Schiff\u2019s base\/fly ash for reactive blue 19 dye removal: Characterization and parametric optimization","volume":"169","author":"Alia","year":"2024","journal-title":"Inorg. Chem. Commun."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"6","DOI":"10.15227\/orgsyn.006.0006","article-title":"Benzil","volume":"6","author":"Clarke","year":"1926","journal-title":"Org. Synth."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"7124","DOI":"10.1039\/C9OB01339C","article-title":"Hydantoin analogs inhibit the fully assembled ClpXP protease without affecting the individual peptidase and chaperone domains","volume":"17","author":"Fetzer","year":"2019","journal-title":"Org. Biomol. Chem."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"407","DOI":"10.1248\/cpb.c20-00857","article-title":"D Direct N1-Selective Alkylation of Hydantoins Using Potassium Bases","volume":"69","author":"Shintani","year":"2021","journal-title":"Chem. Pharm. Bull."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"29","DOI":"10.3998\/ark.5550190.0008.304","article-title":"Evaluating the one-pot synthesis of hydantoins","volume":"2007","author":"Mahmoodi","year":"2007","journal-title":"Arkivoc"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"1451","DOI":"10.1007\/s00706-012-0791-8","article-title":"Synthesis, structural and biological characterization of 5-phenylhydantoin derivatives as potential anticonvulsant agents","volume":"143","author":"Rogan","year":"2012","journal-title":"Monatsh. Chem."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"1490","DOI":"10.1007\/s00044-010-9392-4","article-title":"Synthesis characterization and biological evaluation of some alkoxyphthalimide derivatives of 3-(4-substituted phenyl)-6,6-diphenyl-3,3a-dihydro-2H-imidazo[2,1-b]pyrazolo[3,4-d][1,3]thiazol-7(6H)-one","volume":"20","author":"Dangi","year":"2010","journal-title":"Med. Chem. Res."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"1007","DOI":"10.1002\/jhet.165","article-title":"5,5-diaryl and 5-alkyl-3-phenyl-4-imidazolidones: A novel synthesis","volume":"46","author":"Khurana","year":"2009","journal-title":"J. Heterocycl. Chem."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"4558","DOI":"10.1016\/j.tetlet.2011.06.092","article-title":"Aziridines in one step from hydantoins via Red-Al mediated ring-contraction","volume":"52","author":"Kieseritzky","year":"2011","journal-title":"Tetrahedron Lett."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"3413","DOI":"10.1002\/jps.23141","article-title":"Mechanism of Nanoparticle Formation from Ternary Coground Phenytoin and Its Derivatives","volume":"101","author":"Moribe","year":"2012","journal-title":"J. Pharm. Sci."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/27\/17\/7723\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,9,3]],"date-time":"2026-09-03T04:38:31Z","timestamp":1788410311000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/27\/17\/7723"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,8,28]]},"references-count":52,"journal-issue":{"issue":"17","published-online":{"date-parts":[[2026,9]]}},"alternative-id":["ijms27177723"],"URL":"https:\/\/doi.org\/10.3390\/ijms27177723","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,8,28]]}}}