PUBLICATION
N-Benzyl-(2,5-dioxopyrrolidin-1-yl)propanamide (AS-1) with Hybrid Structure as a Candidate for a Broad-Spectrum Antiepileptic Drug
- Authors
- Kamiński, K., Socała, K., Zagaja, M., Andres-Mach, M., Abram, M., Jakubiec, M., Pieróg, M., Nieoczym, D., Rapacz, A., Gawel, K., Esguerra, C.V., Latacz, G., Lubelska, A., Szulczyk, B., Szewczyk, A., Łuszczki, J.J., Wlaź, P.
- ID
- ZDB-PUB-190906-3
- Date
- 2019
- Source
- Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics 17(1): 309-328 (Journal)
- Registered Authors
- Esguerra, Camila V., Gawel, Kinga Aurelia
- Keywords
- ADME-Tox properties, Drug-resistant epilepsy, PTZ-kindling model of epilepsy, electrophysiology, isobolographic studies, zebrafish
- MeSH Terms
-
- Animals
- Anticonvulsants/administration & dosage*
- Anticonvulsants/chemistry*
- Behavior, Animal/drug effects
- Dose-Response Relationship, Drug
- Epilepsy/chemically induced
- Epilepsy/drug therapy*
- Ethosuximide/chemistry
- Lacosamide/chemistry
- Levetiracetam/chemistry
- Male
- Mice
- Pentylenetetrazole/administration & dosage
- Pyrrolidines/administration & dosage
- Pyrrolidines/chemistry
- Seizures/chemically induced
- Seizures/drug therapy*
- Valproic Acid/administration & dosage
- Zebrafish
- PubMed
- 31486023 Full text @ Neurotherapeutics
Citation
Kamiński, K., Socała, K., Zagaja, M., Andres-Mach, M., Abram, M., Jakubiec, M., Pieróg, M., Nieoczym, D., Rapacz, A., Gawel, K., Esguerra, C.V., Latacz, G., Lubelska, A., Szulczyk, B., Szewczyk, A., Łuszczki, J.J., Wlaź, P. (2019) N-Benzyl-(2,5-dioxopyrrolidin-1-yl)propanamide (AS-1) with Hybrid Structure as a Candidate for a Broad-Spectrum Antiepileptic Drug. Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics. 17(1):309-328.
Abstract
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 PTZ-induced seizures in mice. Thus, AS-1 may 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 μM, as well as no hepatotoxic properties in HepG2 cells (concentration of 10 μM).
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping