C-11, a New Antiepileptic Drug Candidate : Evaluation of the Physicochemical Properties and Impact on the Protective Action of Selected Antiepileptic Drugs in the Mouse Maximal Electroshock-Induced Seizure Model

2021
journal article
article
6
dc.abstract.enC-11 is a hybrid compound derived from 2-(2,5-dioxopyrrolidin-1-yl) propanamide, with a wide spectrum of anticonvulsant activity and low neurotoxicity. The aim of this study was to determine the effects of C-11 on the protective action of various antiepileptic drugs (i.e., carbamazepine CBZ, lacosamide LCM, lamotrigine LTG, and valproate VPA) against maximal electroshock-induced seizures (MES) in mice, as well as its neuroprotective and physicochemical/pharmacokinetic properties. Results indicate that C-11 (30 mg/kg, i.p.) significantly enhanced the anticonvulsant action of LCM (p < 0.001) and VPA (p < 0.05) but not that of CBZ and LTG in the MES test. Neither C-11 (30 mg/kg) alone nor its combination with other anticonvulsant drugs (at their ED50 values from the MES test) affected motor coordination; skeletal muscular strength and long-term memory, as determined in the chimney; grip strength and passive avoidance tests, respectively. Pharmacokinetic characterization revealed that C-11 had no impact on total brain concentrations of LCM or VPA in mice. Qualitative analysis of neuroprotective properties of C-11, after a single administration of pilocarpine, revealed no protective effect of this substance in the tested animals. Determination of physicochemical descriptors showed that C-11 meets the drug-likeness requirements resulting from Lipinski and Veber’s rules and prediction of gastrointestinal absorption and brain penetration, which is extremely important for the CNS-active compounds.
dc.affiliationWydział Farmaceutyczny : Zakład Chemii Lekówpl
dc.cm.date2021-07-16
dc.cm.id104817
dc.cm.idOmegaUJCMa60b0f3e618043a6acdd96934861cf39pl
dc.contributor.authorZagaja, Mirosławpl
dc.contributor.authorSzewczyk, Aleksandrapl
dc.contributor.authorSzala-Rycaj, Joannapl
dc.contributor.authorRaszewski, Grzegorzpl
dc.contributor.authorChrościńska-Krawczyk, Magdalenapl
dc.contributor.authorAbram, Michał - 178828 pl
dc.contributor.authorKamiński, Krzysztof - 129989 pl
dc.contributor.authorAndres-Mach, Martapl
dc.date.accession2021-06-29pl
dc.date.accessioned2021-07-16T10:17:25Z
dc.date.available2021-07-16T10:17:25Z
dc.date.issued2021pl
dc.date.openaccess0
dc.description.accesstimew momencie opublikowania
dc.description.number11pl
dc.description.points100
dc.description.versionostateczna wersja wydawcy
dc.description.volume26pl
dc.identifier.articleid3144pl
dc.identifier.doi10.3390/molecules26113144pl
dc.identifier.eissn1420-3049pl
dc.identifier.issn1420-3049pl
dc.identifier.projectROD UJ / Opl
dc.identifier.urihttps://ruj.uj.edu.pl/xmlui/handle/item/276307
dc.identifier.weblinkhttps://www.mdpi.com/1420-3049/26/11/3144
dc.languageengpl
dc.language.containerengpl
dc.pbn.affiliationDziedzina nauk medycznych i nauk o zdrowiu : nauki farmaceutyczne
dc.relation.uri*
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.typeOtwarte czasopismo
dc.subject.enantiepileptic drugs
dc.subject.enmaximal electroshock-induced seizures
dc.subject.enpharmacokinetic/pharmacodynamic interaction
dc.subject.enneuroprotection
dc.subject.enphysicochemical descriptors
dc.subtypeArticlepl
dc.titleC-11, a New Antiepileptic Drug Candidate : Evaluation of the Physicochemical Properties and Impact on the Protective Action of Selected Antiepileptic Drugs in the Mouse Maximal Electroshock-Induced Seizure Modelpl
dc.title.journalMoleculespl
dc.typeJournalArticlepl
dspace.entity.typePublication
dc.abstract.en
C-11 is a hybrid compound derived from 2-(2,5-dioxopyrrolidin-1-yl) propanamide, with a wide spectrum of anticonvulsant activity and low neurotoxicity. The aim of this study was to determine the effects of C-11 on the protective action of various antiepileptic drugs (i.e., carbamazepine CBZ, lacosamide LCM, lamotrigine LTG, and valproate VPA) against maximal electroshock-induced seizures (MES) in mice, as well as its neuroprotective and physicochemical/pharmacokinetic properties. Results indicate that C-11 (30 mg/kg, i.p.) significantly enhanced the anticonvulsant action of LCM (p < 0.001) and VPA (p < 0.05) but not that of CBZ and LTG in the MES test. Neither C-11 (30 mg/kg) alone nor its combination with other anticonvulsant drugs (at their ED50 values from the MES test) affected motor coordination; skeletal muscular strength and long-term memory, as determined in the chimney; grip strength and passive avoidance tests, respectively. Pharmacokinetic characterization revealed that C-11 had no impact on total brain concentrations of LCM or VPA in mice. Qualitative analysis of neuroprotective properties of C-11, after a single administration of pilocarpine, revealed no protective effect of this substance in the tested animals. Determination of physicochemical descriptors showed that C-11 meets the drug-likeness requirements resulting from Lipinski and Veber’s rules and prediction of gastrointestinal absorption and brain penetration, which is extremely important for the CNS-active compounds.
dc.affiliationpl
Wydział Farmaceutyczny : Zakład Chemii Leków
dc.cm.date
2021-07-16
dc.cm.id
104817
dc.cm.idOmegapl
UJCMa60b0f3e618043a6acdd96934861cf39
dc.contributor.authorpl
Zagaja, Mirosław
dc.contributor.authorpl
Szewczyk, Aleksandra
dc.contributor.authorpl
Szala-Rycaj, Joanna
dc.contributor.authorpl
Raszewski, Grzegorz
dc.contributor.authorpl
Chrościńska-Krawczyk, Magdalena
dc.contributor.authorpl
Abram, Michał - 178828
dc.contributor.authorpl
Kamiński, Krzysztof - 129989
dc.contributor.authorpl
Andres-Mach, Marta
dc.date.accessionpl
2021-06-29
dc.date.accessioned
2021-07-16T10:17:25Z
dc.date.available
2021-07-16T10:17:25Z
dc.date.issuedpl
2021
dc.date.openaccess
0
dc.description.accesstime
w momencie opublikowania
dc.description.numberpl
11
dc.description.points
100
dc.description.version
ostateczna wersja wydawcy
dc.description.volumepl
26
dc.identifier.articleidpl
3144
dc.identifier.doipl
10.3390/molecules26113144
dc.identifier.eissnpl
1420-3049
dc.identifier.issnpl
1420-3049
dc.identifier.projectpl
ROD UJ / O
dc.identifier.uri
https://ruj.uj.edu.pl/xmlui/handle/item/276307
dc.identifier.weblink
https://www.mdpi.com/1420-3049/26/11/3144
dc.languagepl
eng
dc.language.containerpl
eng
dc.pbn.affiliation
Dziedzina nauk medycznych i nauk o zdrowiu : nauki farmaceutyczne
dc.relation.uri*
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
Otwarte czasopismo
dc.subject.en
antiepileptic drugs
dc.subject.en
maximal electroshock-induced seizures
dc.subject.en
pharmacokinetic/pharmacodynamic interaction
dc.subject.en
neuroprotection
dc.subject.en
physicochemical descriptors
dc.subtypepl
Article
dc.titlepl
C-11, a New Antiepileptic Drug Candidate : Evaluation of the Physicochemical Properties and Impact on the Protective Action of Selected Antiepileptic Drugs in the Mouse Maximal Electroshock-Induced Seizure Model
dc.title.journalpl
Molecules
dc.typepl
JournalArticle
dspace.entity.type
Publication
Affiliations

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