Login Register Cart 0
Generic placeholder image

Current Drug Targets

Editor-in-Chief

ISSN (Print): 1389-4501
ISSN (Online): 1873-5592

Back
Journal Home About Journal Editorial Board Journal Insight Current Issue Volumes/Issues
Subscribe
Mini-Review Article

Epileptic Targets and Drugs: A Mini-Review

Author(s): Teresa Carolliny Moreira Lustoza Rodrigues, Jéssica Paiva de Moura, Aline Matilde Ferreira dos Santos, Alex France M. Monteiro, Simone Mendes Lopes, Marcus Tullius Scotti and Luciana Scotti*

Volume 24, Issue 3, 2023

Published on: 27 October, 2022

Page: [212 - 224] Pages: 13

DOI: 10.2174/1389450123666220927103715

Price: $65

Abstract

Background: Epilepsy is a neurological disease affected by an imbalance of inhibitory and excitatory signaling in the brain.

Introduction: In this disease, the targets are active in pathophysiology and thus can be used as a focus for pharmacological treatment.

Methods: Several studies demonstrated the antiepileptic effect of drugs acting on the following targets: N-methyl-D-aspartate (NMDA), alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor, voltage-gated calcium channel (Cav), Gamma aminobutyric acid transporter type 1 (GAT1), voltage-gated sodium channels (Nav), voltage-gated potassium channel of the Q subfamily (KCNQ) and Gamma aminobutyric acid type A (GABAA) receiver.

Results: These studies highlight the importance of molecular docking.

Conclusion: Quantitative Structure-Activity Relationship (QSAR) and computer aided drug design (CADD) in predicting of possible pharmacological activities of these targets.

Keywords: Molecular docking, AMPA, NMDA, GAT1, KCNQ, Cav, Nav e GABAA

« Previous Next »
Graphical Abstract

[1]
Basu T, Maguire J, Salpekar JA. Hypothalamic-pituitary-adrenal axis targets for the treatment of epilepsy. Neurosci Lett 2021; 746: 135618.
[http://dx.doi.org/10.1016/j.neulet.2020.135618] [PMID: 33429002]
[2]
Li Y, Ding Y, Xiao W, Zhu J. Investigation on the active ingredient and mechanism of Cannabis sativa L. for treating epilepsy based on network pharmacology. Biotechnol Biotechnol Equip 2021; 35(1): 994-1009.
[http://dx.doi.org/10.1080/13102818.2021.1942208]
[3]
Sari S, Barut B, Marcinkowska M, et al. Potential of nafimidone derivatives against co-morbidities of epilepsy  In vitro, in vivo, and in silico investigations. Drug Dev Res 2021; 83(1): 184-93.
[4]
Ishibashi M, Egawa K, Fukuda A. Diverse actions of astrocytes in GABAergic signaling. Int J Mol Sci 2019; 20(12): 1-18.
[http://dx.doi.org/10.3390/ijms20122964] [PMID: 31216630]
[5]
Marafiga RJ, Pasquetti VM, Calcagnotto ME. GABAergic interneurons in epilepsy: More than a simple change in inhibition. Epilepsy Behav 2021; 121(Pt B): 106935.
[http://dx.doi.org/10.1016/j.yebeh.2020.106935] [PMID: 32035792]
[6]
Sazhina TA, Sitovskaya DA, Zabrodskaya YM, Bazhanova ED. Functional imbalance of glutamate- and gabaergic neuronal systems in the pathogenesis of focal drug-resistant epilepsy in humans. Bull Exp Biol Med 2020; 168(4): 529-32.
[http://dx.doi.org/10.1007/s10517-020-04747-3] [PMID: 32147766]
[7]
Ghosh S, Sinha JK, Khan T, et al. Pharmacological and therapeutic approaches in the treatment of epilepsy. Biomedicines 2021; 9(5): 1-14.
[http://dx.doi.org/10.3390/biomedicines9050470] [PMID: 33923061]
[8]
Lhatoo SD, Bernasconi N, Blumcke I, et al. Big data in epilepsy: Clinical and research considerations. Report from the epilepsy big data task force of the international league against epilepsy. Epilepsia 2020; 61(9): 1869-83.
[http://dx.doi.org/10.1111/epi.16633] [PMID: 32767763]
[9]
Fisher RS, Cross JH, D’Souza C, et al. Instruction manual for the ILAE 2017 operational classification of seizure types. Epilepsia 2017; 58(4): 531-42.
[http://dx.doi.org/10.1111/epi.13671] [PMID: 28276064]
[10]
Devinsky O, Vezzani A, O’Brien TJ, et al. Epilepsy. Nat Rev Dis Primers 2018; 4: 18024.
[11]
Whelehan A, Colfer M, Kearney H, et al. Location-specific reflex epilepsy: A novel reflex epilepsy phenotype. Epilepsy Behav Rep 2020; 14: 100375.
[http://dx.doi.org/10.1016/j.ebr.2020.100375]
[12]
Gurung AB, Ali MA, Lee J, Farah MA, Al-Anazi KM. An updated review of computer-aided drug design and its application to COVID-19. BioMed Res Int 2021; 2021: 8853056.
[13]
Srivastav AK, Gupta SK, Kumar U. Computational studies towards identification of lead herbal compounds of medicinal importance for development of nutraceutical against COVID-19. ChemRxiv 2020.
[http://dx.doi.org/10.26434/chemrxiv.12581819.v1]
[14]
Wang Z, Huo J, Sun L, et al. Computer-aided drug design for AMP-activated protein kinase activators. Curr Computeraided Drug Des 2011; 7(3): 214-27.
[http://dx.doi.org/10.2174/157340911796504323] [PMID: 21595631]
[15]
Mottini C, Napolitano F, Li Z, Gao X, Cardone L. Computer-aided drug repurposing for cancer therapy: Approaches and opportunities to challenge anticancer targets. Semin Cancer Biol 2021; 68: 59-74.
[http://dx.doi.org/10.1016/j.semcancer.2019.09.023] [PMID: 31562957]
[16]
Obireddy SR, Subbarao SMC, Venkata KRKS, Lai WF. Development and characterization of montmorillonite-based hybrid materials for pH-responsive drug delivery. ChemistrySelect 2021; 6(7): 1466-70.
[http://dx.doi.org/10.1002/slct.202004711]
[17]
Pinto FJ, Fillion A, Duchambon P, Bombard S, Granzhan A. Acridine-O6-benzylguanine hybrids: Synthesis, DNA binding, MGMT inhibition and antiproliferative activity. Eur J Med Chem 2022; 227: 113909.
[http://dx.doi.org/10.1016/j.ejmech.2021.113909] [PMID: 34731767]
[18]
Adamovich SN, Ushakov IA, Oborina EN, Vashchenko AV. Silatrane-sulfonamide hybrids: Synthesis, characterization, and evaluation of biological activity. J Organomet Chem 2022; 957: 957.
[http://dx.doi.org/10.1016/j.jorganchem.2021.122150]
[19]
Supuran CT. Multitargeting approaches involving carbonic anhydrase inhibitors: Hybrid drugs against a variety of disorders. J Enzyme Inhib Med Chem 2021; 36(1): 1702-14.
[http://dx.doi.org/10.1080/14756366.2021.1945049] [PMID: 34325588]
[20]
Góra M, Czopek A, Rapacz A, et al. Synthesis, anticonvulsant and antinociceptive activity of new hybrid compounds: Derivatives of 3-(3-methylthiophen-2-yl)-pyrrolidine-2,5-dione. Int J Mol Sci 2020; 21(16): 1-21.
[http://dx.doi.org/10.3390/ijms21165750] [PMID: 32796594]
[21]
Singh RB, Singh GK, Chaturvedi K, Kumar D, Singh SK, Zaman MK. Design, synthesis, characterization, and molecular modeling studies of novel oxadiazole derivatives of nipecotic acid as potential anticonvulsant and antidepressant agents. Med Chem Res 27(1): 137-52.
[http://dx.doi.org/10.1007/s00044-017-2047-y]
[22]
Lamie PF, El-Kalaawy AM, Latif ANS, Rashed LA, Philoppes JN. Pyrazolo[3,4-d]pyrimidine-based dual EGFR T790M/HER2 inhibitors: Design, synthesis, structure-activity relationship and biological activity as potential antitumor and anticonvulsant agents. Eur J Med Chem 2021; 214: 113222.
[http://dx.doi.org/10.1016/j.ejmech.2021.113222] [PMID: 33545637]
[23]
Mishchenko M, Shtrygol S, Kaminskyy D, Lesyk R. Thiazole-bearing 4-thiazolidinones as new anticonvulsant agents. Sci Pharm 2020; 88(1): 16.
[http://dx.doi.org/10.3390/scipharm88010016]
[24]
Siddiqui AA, Partap S, Khisal S, Yar MS, Mishra R. Synthesis, anti-convulsant activity and molecular docking study of novel thiazole pyridazinone hybrid analogues. Bioorg Chem 2020; 99: 103584.
[http://dx.doi.org/10.1016/j.bioorg.2020.103584] [PMID: 32229345]
[25]
Kamiński K, Socała K, Zagaja M, et al. N-benzyl-(2,5-dioxopyrrolidin-1-yl)propanamide (AS-1) with hybrid structure as a candidate for a broad-spectrum antiepileptic drug. Neurotherapeutics 2020; 17(1): 309-28.
[http://dx.doi.org/10.1007/s13311-019-00773-w] [PMID: 31486023]
[26]
Masiulis S, Desai R, Uchański T, et al. Europe PMC Funders Group Europe PMC Funders Author Manuscripts GABA A receptor signalling mechanisms revealed by structural pharmacology. Nature 2019; 565(7740): 454-9.
[27]
Mareš P, Kubová H. Interaction of GABAA and GABAB antagonists after status epilepticus in immature rats. Epilepsy Behav 2020; 102: 106683.
[http://dx.doi.org/10.1016/j.yebeh.2019.106683] [PMID: 31760199]
[28]
Kim JJ, Gharpure A, Teng J, et al. Shared structural mechanisms of general anaesthetics and benzodiazepines. Nature 2020; 585(7824): 303-8.
[http://dx.doi.org/10.1038/s41586-020-2654-5] [PMID: 32879488]
[29]
Malyshev AV, Sukhanova IA, Zlobin AS, et al. In silico screening and behavioral validation of a novel peptide, LCGA-17, with anxiolytic-like properties. Front Neurosci 2021; 15: 705590.
[http://dx.doi.org/10.3389/fnins.2021.705590] [PMID: 34421525]
[30]
Xavier J da C, Ferreira MKA, da Silva AW. Anxiolytic-like and anticonvulsant effect in adult zebrafish (Danio rerio) through gabaergic system and molecular docking study of chalcone derived from natural products. Biointerface Res Appl Chem 2021; 11(6): 14021-31.
[http://dx.doi.org/10.33263/BRIAC116.1402114031]
[31]
Zaręba P, Sałat K, Höfner GC, et al. Development of tricyclic Nbenzyl-4-hydroxybutanamide derivatives as inhibitors of GABA transporters mGAT1-4 with anticonvulsant, antinociceptive, and antidepressant activity. Eur J Med Chem 2021; 221: 113512.
[http://dx.doi.org/10.1016/j.ejmech.2021.113512] [PMID: 34015586]
[32]
Andrade JC, Monteiro ÁB, Andrade HHN, et al. Involvement of GABA a receptors in the anxiolytic-like effect of hydroxycitronellal. BioMed Res Int 2021; 2021: 9929805.
[33]
da Silva AW, Ferreira MKA, Pereira LR, et al. Combretum lanceolatum extract reverses anxiety and seizure behavior in adult zebrafish through GABAergic neurotransmission: An in vivo and in silico study. J Biomol Struct Dyn 2021; 14: 1-14.
[http://dx.doi.org/10.1080/07391102.2021.1935322] [PMID: 34121622]
[34]
Shafie A, Mohammadi-Khanaposhtani M, Asadi M, et al. Novel fused 1,2,3-triazolo-benzodiazepine derivatives as potent anticonvulsant agents: Design, synthesis, in vivo, and in silico evaluations. Mol Divers 2020; 24(1): 179-89.
[http://dx.doi.org/10.1007/s11030-019-09940-9] [PMID: 30895449]
[35]
Emami S, Valipour M, Komishani KF, et al. Synthesis, in silico, in vitro and in vivo evaluations of isatin aroylhydrazones as highly potent anticonvulsant agents. Bioorg Chem 2021; 112: 104943.
[36]
Eibl C, Plested AJR. AMPA receptors: Mechanisms of auxiliary protein action. Curr Opin Physiol 2018; 2: 84-91.
[http://dx.doi.org/10.1016/j.cophys.2017.12.009]
[37]
Witkin JM, Knutson DE, Rodriguez GJ, Shi S. Rapid-acting antidepressants. Curr Pharm Des 2018; 24(22): 2556-63.
[http://dx.doi.org/10.2174/1381612824666180730104707] [PMID: 30058481]
[38]
Abulkhair HS, Elmeligie S, Ghiaty A, et al. in vivo and in silico driven identification of novel synthetic quinoxalines as anticonvulsants and AMPA inhibitors. Arch Pharm (Weinheim) 2021; 354(5): e2000449.
[http://dx.doi.org/10.1002/ardp.202000449] [PMID: 33559320]
[39]
Valipour M, Naderi N, Heidarli E, et al. Design, synthesis and biological evaluation of naphthalene-derived (arylalkyl)azoles containing heterocyclic linkers as new anticonvulsants: A comprehensive in silico, in vitro, and in vivo study. Eur J Pharm Sci 2021; 166: 105974.
[http://dx.doi.org/10.1016/j.ejps.2021.105974] [PMID: 34390829]
[40]
Duan ML, Tan LL, Du J, Yao XJ. Structure based virtual screening of novel noncompetitive antagonist of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor. J Biotechnol 2019; 295: 9-18.
[http://dx.doi.org/10.1016/j.jbiotec.2019.01.023] [PMID: 30831124]
[41]
El-Helby AA, Ayyad RRA, El-Adl K, Elkady H. Phthalazine-1,4-dione derivatives as non-competitive AMPA receptor antagonists: Design, synthesis, anticonvulsant evaluation, ADMET profile and molecular docking. Mol Divers 2019; 23(2): 283-98.
[http://dx.doi.org/10.1007/s11030-018-9871-y] [PMID: 30168051]
[42]
Mehta P, Srivastava S, Sharma M, Malik R. Discovery of novel chemotypes for competitive AMPA receptor antagonists as potential antiepileptic agents through structure-based virtual screening of natural products library. Struct Chem 2019; 30(4): 1159-72.
[http://dx.doi.org/10.1007/s11224-018-1269-z]
[43]
Kowalska M, Fijałkowski Ł, Kubacka M, et al. Antiepileptic drug tiagabine does not directly target key cardiac ion channels kv11.1, nav1.5 and cav1.2. Molecules 2021; 26(12): 3522.
[http://dx.doi.org/10.3390/molecules26123522] [PMID: 34207748]
[44]
Rangel-Galván M, Rangel A, Romero-Méndez C, et al. Inhibitory mechanism of the isoflavone derivative genistein in the human CaV3.3 channel. ACS Chem Neurosci 2021; 12(4): 651-9.
[http://dx.doi.org/10.1021/acschemneuro.0c00684] [PMID: 33507062]
[45]
Fattorini G, Melone M, Conti F. A reappraisal of GAT-1 localization in neocortex. Front Cell Neurosci 2020; 14: 9.
[http://dx.doi.org/10.3389/fncel.2020.00009] [PMID: 32116556]
[46]
Dayan O, Nagarajan A, Shah R, Ben-Yona A, Forrest LR, Kanner BI. An extra amino acid residue in transmembrane domain 10 of the γ-aminobutyric acid (GABA) transporter GAT-1 is required for efficient ion-coupled transport. J Biol Chem 2017; 292(13): 5418-28.
[http://dx.doi.org/10.1074/jbc.M117.775189] [PMID: 28213519]
[47]
Lyu S, Guo Y, Zhang L, et al. Blockade of GABA transporter-1 and GABA transporter-3 in the lateral habenula improves depressive-like behaviors in a rat model of Parkinson’s disease. Neuropharmacology 2020; 181: 108369.
[http://dx.doi.org/10.1016/j.neuropharm.2020.108369] [PMID: 33096108]
[48]
de Aquino PEA, Bezerra RJ, de Souza Nascimento T, et al. A proline derivative-enriched fraction from sideroxylon obtusifolium protects the hippocampus from intracerebroventricular pilocarpine-induced injury associated with Status epilepticus in mice. Int J Mol Sci 2020; 21(11): 4188.
[http://dx.doi.org/10.3390/ijms21114188] [PMID: 32545390]
[49]
Singh RB, Das N, Singh GK, Singh SK, Zaman K. Synthesis and pharmacological evaluation of 3-[5-(aryl-[1,3,4]oxadiazole-2-yl]-piperidine derivatives as anticonvulsant and antidepressant agents. Arab J Chem 2020; 13(5): 5299-311.
[http://dx.doi.org/10.1016/j.arabjc.2020.03.009]
[50]
Zafar S, Jabeen I. GRID-independent molecular descriptor analysis and molecular docking studies to mimic the binding hypothesis of γ-aminobutyric acid transporter 1 (GAT1) inhibitors. PeerJ 2019; 7(1): e6283.
[http://dx.doi.org/10.7717/peerj.6283] [PMID: 30723616]
[51]
Nowaczyk A. Fijałkowski Ł Kowalska M, Podkowa A, Sałat K. Studies on the activity of selected highly lipophilic compounds toward hGAT1 inhibition. Part II. ACS Chem Neurosci 2019; 10(1): 337-47.
[http://dx.doi.org/10.1021/acschemneuro.8b00282] [PMID: 30222312]
[52]
Brodie MJ. Sodium channel blockers in the treatment of epilepsy. CNS Drugs 2017; 31(7): 527-34.
[http://dx.doi.org/10.1007/s40263-017-0441-0] [PMID: 28523600]
[53]
Kurata HT. Chemical regulation of Kv7 channels: Diverse scaffolds, sites, and mechanisms of action. J Gen Physiol 2020; 152(8): e202012598.
[http://dx.doi.org/10.1085/jgp.202012598] [PMID: 32484852]
[54]
Redford KE, Abbott GW. The ubiquitous flavonoid quercetin is an atypical KCNQ potassium channel activator. Commun Biol 2020; 3(1): 356.
[http://dx.doi.org/10.1038/s42003-020-1089-8] [PMID: 32641720]
[55]
Shi S, Li J, Sun F, et al. Molecular mechanisms and structural basis of retigabine analogues in regulating KCNQ2 channel. J Membr Biol 2020; 253(2): 167-81.
[http://dx.doi.org/10.1007/s00232-020-00113-6] [PMID: 32170353]
[56]
Manville RW, Abbott GW. Cilantro leaf harbors a potent potassium channel-activating anticonvulsant. FASEB J 2019; 33(10): 11349-63.
[http://dx.doi.org/10.1096/fj.201900485R] [PMID: 31311306]
[57]
Deuis JR, Mueller A, Israel MR, Vetter I. The pharmacology of voltage-gated sodium channel activators. Neuropharmacology 2017; 127: 87-108.
[http://dx.doi.org/10.1016/j.neuropharm.2017.04.014] [PMID: 28416444]
[58]
Ghovanloo MR, Aimar K, Ghadiry-Tavi R, Yu A, Ruben PC. Physiology and pathophysiology of sodium channel inactivation. Curr Top Membr 2016; 78: 479-509.
[http://dx.doi.org/10.1016/bs.ctm.2016.04.001] [PMID: 27586293]
[59]
Liu Z, Wadsworth P, Singh AK, et al. Bioorganic & medicinal chemistry letters identification of peptidomimetics as novel chemical probes modulating (Nav1 . 6) protein-protein interactions. 2019; 29: 413-9.
[60]
Najm S, Naureen H, Sultana K, et al. In-silico computational analysis of [6-(2, 3-dichlorophenyl)-1, 2, 4-triazine-3, 5-diamine] metal complexes on voltage gated sodium channel and dihydrofolate reductase enzyme. Pak J Pharm Sci 2020; 33(4) (Suppl.): 1779-86.
[PMID: 33612461]
[61]
Sabatier LL, Palestro PH, Enrique AV, et al. Design, synthesis and biological evaluation of N-substituted α-hydroxyimides and 1,2,3-oxathiazolidine-4-one-2,2-dioxides with anticonvulsant activity. J Enzyme Inhib Med Chem 2019; 34(1): 1465-73.
[http://dx.doi.org/10.1080/14756366.2019.1651722] [PMID: 31411081]
[62]
Pooventhiran T, Bhattacharyya U, Rao DJ, et al. Detailed spectra, electronic properties, qualitative non-covalent interaction analysis, solvatochromism, docking and molecular dynamics simulations in different solvent atmosphere of cenobamate. Struct Chem 2020; 31(6): 2475-85.
[http://dx.doi.org/10.1007/s11224-020-01607-8]
[63]
Scheffer IE, Nabbout R. SCN1A-related phenotypes: Epilepsy and beyond. Epilepsia 2019; 60(S3): S17-24.
[http://dx.doi.org/10.1111/epi.16386] [PMID: 31904117]
[64]
Menezes LFS, Sabiá Júnior EF, Tibery DV, Carneiro LDA, Schwartz EF. Epilepsy-related voltage-gated sodium channelopathies: A review. Front Pharmacol 2020; 11: 1276.
[http://dx.doi.org/10.3389/fphar.2020.01276] [PMID: 33013363]
[65]
DeKeyser JM, Thompson CH, George AL Jr. Cryptic prokaryotic promoters explain instability of recombinant neuronal sodium channels in bacteria. J Biol Chem 2021; 296: 100298.
[http://dx.doi.org/10.1016/j.jbc.2021.100298] [PMID: 33460646]
[66]
Mason ER, Wu F, Patel RR, Xiao Y, Cannon SC, Cummins TR. Resurgent and gating pore currents induced by de novo SCN2A epilepsy mutations. eNeuro 2019; 6(5): ENEURO.0141-19.2019.
[http://dx.doi.org/10.1523/ENEURO.0141-19.2019] [PMID: 31558572]
[67]
Suleimanova A, Talanov M, van den Maagdenberg AMJM, Giniatullin R. Deciphering in silico the role of mutated na v 1.1 sodium channels in enhancing trigeminal nociception in familial hemiplegic migraine type 3. Front Cell Neurosci 2021; 15: 644047.
[http://dx.doi.org/10.3389/fncel.2021.644047] [PMID: 34135733]
[68]
Kaproń B, Łuszczki JJ, Płazińska A, et al. Development of the 1,2,4-triazole-based anticonvulsant drug candidates acting on the voltage-gated sodium channels. Insights from in-vivo, in-vitro, and in-silico studies. Eur J Pharm Sci 2019; 129(129): 42-57.
[http://dx.doi.org/10.1016/j.ejps.2018.12.018] [PMID: 30594731]
[69]
Zhou H-X, Wollmuth LP. Advancing NMDA receptor physiology by integrating multiple approaches. Trends Neurosci 2017; 40(3): 129-37.
[http://dx.doi.org/10.1016/j.tins.2017.01.001] [PMID: 28187950]
[70]
Katzman BM, Perszyk RE, Yuan H, et al. A novel class of negative allosteric modulators of NMDA receptor function. Bioorg Med Chem Lett 2015; 25(23): 5583-8.
[http://dx.doi.org/10.1016/j.bmcl.2015.10.046] [PMID: 26525866]
[71]
Vyklicky V, Korinek M, Smejkalova T, et al. Structure, function, and pharmacology of NMDA receptor channels. Physiol Res 2014; 63 (Suppl. 1): S191-203.
[http://dx.doi.org/10.33549/physiolres.932678] [PMID: 24564659]
[72]
Schultz KJ, Colby SM, Yesiltepe Y, Nuñez JR, McGrady MY, Renslow RS. Application and assessment of deep learning for the generation of potential NMDA receptor antagonists. Phys Chem Chem Phys 2021; 23(2): 1197-214.
[http://dx.doi.org/10.1039/D0CP03620J] [PMID: 33355332]
[73]
Gawel K, Kukula-Koch W, Banono NS, et al. 6-Gingerol, a major constituent of Zingiber officinale rhizoma, exerts anticonvulsant activity in the pentylenetetrazole-induced seizure model in larval zebrafish. Int J Mol Sci 2021; 22(14): 7745.
[http://dx.doi.org/10.3390/ijms22147745] [PMID: 34299361]

Rights & Permissions Print Cite
Article Metrics
1
© 2024 Bentham Science Publishers | Privacy Policy