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

doi:10.1007/s13311-019-00773-w

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

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

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Bibliographic description

punktacja MEiN [2020]: 140

title:	N-Benzyl-(2,5-dioxopyrrolidin-1-yl)propanamide (AS-1) with hybrid structure as a candidate for a broad-spectrum antiepileptic drug
author:	Kamiński Krzysztof , Socała Katarzyna, Zagaja Mirosław, Andres-Mach Marta, Abram Michał , Jakubiec Marcin , Pieróg Mateusz, Nieoczym Dorota, Rapacz Anna , Gaweł Kinga, Esguerra Camila V., Latacz Gniewomir , Lubelska Annamaria , Szulczyk Bartłomiej, Szewczyk Aleksandra, Łuszczki Jarogniew Jacek, Wlaź Piotr
journal title:	Neurotherapeutics
volume:	20
issue:	1
date of publication :	2020
pages:	309-328
ISSN:	1933-7213
eISSN:	1878-7479
DOI:	10.1007/s13311-019-00773-w
URL:	https://link.springer.com/article/10.1007/s13311-019-00773-w
date accessed:	2020-12-08
notes:	Bibliogr. s. 326-328
language:	English
journal language:	English
abstract in English:	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).
keywords in English:	drug-resistant epilepsy, PTZ-kindling model of epilepsy, isobolographic studies, electrophysiology, ADME-Tox properties, zebrafish
departmental parameterization:	140
affiliation:	Wydział Farmaceutyczny : Zakład Chemii Leków, Wydział Farmaceutyczny : Zakład Farmakodynamiki, Wydział Farmaceutyczny : Zakład Technologii i Biotechnologii Środków Leczniczych, Szkoła Doktorska Nauk Medycznych i Nauk o Zdrowiu
type:	journal article
subtype:	academic paper