N-Benzyl-(2,5-dioxopyrrolidin-1-yl)propanamide (AS-1) with hybrid structure as a candidate for a broad-spectrum antiepileptic drug

2020
journal article
article
21
cris.lastimport.wos2024-04-09T18:48:52Z
dc.abstract.enIn our recent studies, we identified compound N-benzyl-2-(2,5-dioxopyrrolidin-1-yl)propanamide (AS-1) as a broad-spectrum hybrid anticonvulsant which showed potent protection across the most important animal acute seizure models such as the maximal electroshock (MES) test, the subcutaneous pentylenetetrazole (s.c. PTZ) test, and the 6-Hz (32 mA) test in mice. Therefore, AS-1 may be recognized as a candidate for new anticonvulsant effective in different types of human epilepsy with a favorable safety margin profile determined in the rotarod test in mice. In the aim of further pharmacological evaluation of AS-1, in the current study, we examined its activity in the 6-Hz (44 mA) test, which is known as the model of drug-resistant epilepsy. Furthermore, we determined also the antiseizure activity in the kindling model of epilepsy induced by repeated injection of pentylenetetrazole (PTZ) in mice. As a result, AS-1 revealed relatively potent protection in the 6-Hz (44 mA) test, as well as delayed the progression of kindling induced by repeated injection of PTZ in mice at doses of 15 mg/kg, 30 mg/kg, and 60 mg/kg. Importantly, the isobolographic analysis showed that a combination of AS-1 and valproic acid (VPA) at the fixed ratio of 1:1 displayed a supra-additive (synergistic) interaction against PTZinduced seizures inmice. Thus, AS-1may be potentially used in an add-on therapy with VPA. Moreover, incubation of zebrafish larvae with AS-1 substantially decreased the number, cumulative but not the mean duration of epileptiform-like events in electroencephalographic assay. Finally, the in vitro ADME-Tox studies revealed that AS-1 is characterized by a very good permeability in the parallel artificial membrane permeability assay test, excellent metabolic stability on human liver microsomes (HLMs), no significant influence on CYP3A4/CYP2D6 activity, and moderate inhibition of CYP2C9 in a concentration of 10 $\mu$M, as well as no hepatotoxic properties in HepG2 cells (concentration of 10 $\mu$M).pl
dc.affiliationWydział Farmaceutyczny : Zakład Chemii Lekówpl
dc.affiliationWydział Farmaceutyczny : Zakład Farmakodynamikipl
dc.affiliationWydział Farmaceutyczny : Zakład Technologii i Biotechnologii Środków Leczniczychpl
dc.affiliationSzkoła Doktorska Nauk Medycznych i Nauk o Zdrowiupl
dc.cm.date2020-12-02
dc.cm.id96002
dc.contributor.authorKamiński, Krzysztof - 129989 pl
dc.contributor.authorSocała, Katarzynapl
dc.contributor.authorZagaja, Mirosławpl
dc.contributor.authorAndres-Mach, Martapl
dc.contributor.authorAbram, Michał - 178828 pl
dc.contributor.authorJakubiec, Marcin - 236123 pl
dc.contributor.authorPieróg, Mateuszpl
dc.contributor.authorNieoczym, Dorotapl
dc.contributor.authorRapacz, Anna - 133263 pl
dc.contributor.authorGaweł, Kingapl
dc.contributor.authorEsguerra, Camila V.pl
dc.contributor.authorLatacz, Gniewomir - 200736 pl
dc.contributor.authorLubelska, Annamaria - 223647 pl
dc.contributor.authorSzulczyk, Bartłomiejpl
dc.contributor.authorSzewczyk, Aleksandrapl
dc.contributor.authorŁuszczki, Jarogniew Jacekpl
dc.contributor.authorWlaź, Piotrpl
dc.date.accession2020-12-08pl
dc.date.accessioned2020-12-02T10:07:40Zpl
dc.date.available2020-12-02T10:07:40Zpl
dc.date.issued2020pl
dc.date.openaccess0
dc.description.accesstimew momencie opublikowania
dc.description.additionalBibliogr. s. 326-328pl
dc.description.number1pl
dc.description.physical309-328pl
dc.description.points140pl
dc.description.versionostateczna wersja wydawcy
dc.description.volume20pl
dc.identifier.doi10.1007/s13311-019-00773-wpl
dc.identifier.eissn1878-7479pl
dc.identifier.issn1933-7213pl
dc.identifier.projectROD UJ / OPpl
dc.identifier.urihttps://ruj.uj.edu.pl/xmlui/handle/item/256109
dc.identifier.weblinkhttps://link.springer.com/article/10.1007/s13311-019-00773-wpl
dc.languageengpl
dc.language.containerengpl
dc.rightsUdzielam licencji. Uznanie autorstwa 4.0 Międzynarodowa*
dc.rights.licenceCC-BY
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/legalcode.pl*
dc.share.typeinne
dc.subject.endrug-resistant epilepsypl
dc.subject.enPTZ-kindling model of epilepsypl
dc.subject.enisobolographic studiespl
dc.subject.enelectrophysiologypl
dc.subject.enADME-Tox propertiespl
dc.subject.enzebrafishpl
dc.subtypeArticlepl
dc.titleN-Benzyl-(2,5-dioxopyrrolidin-1-yl)propanamide (AS-1) with hybrid structure as a candidate for a broad-spectrum antiepileptic drugpl
dc.title.journalNeurotherapeuticspl
dc.typeJournalArticlepl
dspace.entity.typePublication
cris.lastimport.wos
2024-04-09T18:48:52Z
dc.abstract.enpl
In our recent studies, we identified compound N-benzyl-2-(2,5-dioxopyrrolidin-1-yl)propanamide (AS-1) as a broad-spectrum hybrid anticonvulsant which showed potent protection across the most important animal acute seizure models such as the maximal electroshock (MES) test, the subcutaneous pentylenetetrazole (s.c. PTZ) test, and the 6-Hz (32 mA) test in mice. Therefore, AS-1 may be recognized as a candidate for new anticonvulsant effective in different types of human epilepsy with a favorable safety margin profile determined in the rotarod test in mice. In the aim of further pharmacological evaluation of AS-1, in the current study, we examined its activity in the 6-Hz (44 mA) test, which is known as the model of drug-resistant epilepsy. Furthermore, we determined also the antiseizure activity in the kindling model of epilepsy induced by repeated injection of pentylenetetrazole (PTZ) in mice. As a result, AS-1 revealed relatively potent protection in the 6-Hz (44 mA) test, as well as delayed the progression of kindling induced by repeated injection of PTZ in mice at doses of 15 mg/kg, 30 mg/kg, and 60 mg/kg. Importantly, the isobolographic analysis showed that a combination of AS-1 and valproic acid (VPA) at the fixed ratio of 1:1 displayed a supra-additive (synergistic) interaction against PTZinduced seizures inmice. Thus, AS-1may be potentially used in an add-on therapy with VPA. Moreover, incubation of zebrafish larvae with AS-1 substantially decreased the number, cumulative but not the mean duration of epileptiform-like events in electroencephalographic assay. Finally, the in vitro ADME-Tox studies revealed that AS-1 is characterized by a very good permeability in the parallel artificial membrane permeability assay test, excellent metabolic stability on human liver microsomes (HLMs), no significant influence on CYP3A4/CYP2D6 activity, and moderate inhibition of CYP2C9 in a concentration of 10 $\mu$M, as well as no hepatotoxic properties in HepG2 cells (concentration of 10 $\mu$M).
dc.affiliationpl
Wydział Farmaceutyczny : Zakład Chemii Leków
dc.affiliationpl
Wydział Farmaceutyczny : Zakład Farmakodynamiki
dc.affiliationpl
Wydział Farmaceutyczny : Zakład Technologii i Biotechnologii Środków Leczniczych
dc.affiliationpl
Szkoła Doktorska Nauk Medycznych i Nauk o Zdrowiu
dc.cm.date
2020-12-02
dc.cm.id
96002
dc.contributor.authorpl
Kamiński, Krzysztof - 129989
dc.contributor.authorpl
Socała, Katarzyna
dc.contributor.authorpl
Zagaja, Mirosław
dc.contributor.authorpl
Andres-Mach, Marta
dc.contributor.authorpl
Abram, Michał - 178828
dc.contributor.authorpl
Jakubiec, Marcin - 236123
dc.contributor.authorpl
Pieróg, Mateusz
dc.contributor.authorpl
Nieoczym, Dorota
dc.contributor.authorpl
Rapacz, Anna - 133263
dc.contributor.authorpl
Gaweł, Kinga
dc.contributor.authorpl
Esguerra, Camila V.
dc.contributor.authorpl
Latacz, Gniewomir - 200736
dc.contributor.authorpl
Lubelska, Annamaria - 223647
dc.contributor.authorpl
Szulczyk, Bartłomiej
dc.contributor.authorpl
Szewczyk, Aleksandra
dc.contributor.authorpl
Łuszczki, Jarogniew Jacek
dc.contributor.authorpl
Wlaź, Piotr
dc.date.accessionpl
2020-12-08
dc.date.accessionedpl
2020-12-02T10:07:40Z
dc.date.availablepl
2020-12-02T10:07:40Z
dc.date.issuedpl
2020
dc.date.openaccess
0
dc.description.accesstime
w momencie opublikowania
dc.description.additionalpl
Bibliogr. s. 326-328
dc.description.numberpl
1
dc.description.physicalpl
309-328
dc.description.pointspl
140
dc.description.version
ostateczna wersja wydawcy
dc.description.volumepl
20
dc.identifier.doipl
10.1007/s13311-019-00773-w
dc.identifier.eissnpl
1878-7479
dc.identifier.issnpl
1933-7213
dc.identifier.projectpl
ROD UJ / OP
dc.identifier.uri
https://ruj.uj.edu.pl/xmlui/handle/item/256109
dc.identifier.weblinkpl
https://link.springer.com/article/10.1007/s13311-019-00773-w
dc.languagepl
eng
dc.language.containerpl
eng
dc.rights*
Udzielam licencji. Uznanie autorstwa 4.0 Międzynarodowa
dc.rights.licence
CC-BY
dc.rights.uri*
http://creativecommons.org/licenses/by/4.0/legalcode.pl
dc.share.type
inne
dc.subject.enpl
drug-resistant epilepsy
dc.subject.enpl
PTZ-kindling model of epilepsy
dc.subject.enpl
isobolographic studies
dc.subject.enpl
electrophysiology
dc.subject.enpl
ADME-Tox properties
dc.subject.enpl
zebrafish
dc.subtypepl
Article
dc.titlepl
N-Benzyl-(2,5-dioxopyrrolidin-1-yl)propanamide (AS-1) with hybrid structure as a candidate for a broad-spectrum antiepileptic drug
dc.title.journalpl
Neurotherapeutics
dc.typepl
JournalArticle
dspace.entity.type
Publication

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