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 |
punktacja MEiN [2020]: 140