The Search for New Anticonvulsants in a Group of (2,5-Dioxopyrrolidin-1-yl)(phenyl)Acetamides with Hybrid Structure-Synthesis and In Vivo/In Vitro Studies.

Michał Abram,Szczepan Mogilski,Gniewomir Latacz,Krzysztof Kamiński,Marcin Jakubiec,Rafał M Kamiński,Anna Rapacz

doi:10.3390/ijms21228780

Michał Abram, Szczepan Mogilski + Show 5 more

Open Access

https://doi.org/10.3390/ijms21228780

Copy DOI

Abstract

Epilepsy belongs to the most common and debilitating neurological disorders with multifactorial pathophysiology and a high level of drug resistance. Therefore, with the aim of searching for new, more effective, and/or safer therapeutics, we discovered a focused series of original hybrid pyrrolidine-2,5-dione derivatives with potent anticonvulsant properties. We applied an optimized coupling reaction yielding several hybrid compounds that showed broad-spectrum activity in widely accepted animal seizure models, namely, the maximal electroshock (MES) test and the psychomotor 6 Hz (32 mA) seizure model in mice. The most potent anticonvulsant activity and favorable safety profile was demonstrated for compound 30 (median effective dose (ED50) MES = 45.6 mg/kg, ED50 6 Hz (32 mA) = 39.5 mg/kg, median toxic dose (TD50) (rotarod test) = 162.4 mg/kg). Anticonvulsant drugs often show activity in pain models, and compound 30 was also proven effective in the formalin test of tonic pain, the capsaicin-induced pain model, and the oxaliplatin (OXPT)-induced neuropathic pain model in mice. Our studies showed that the most plausible mechanism of action of 30 involves inhibition of calcium currents mediated by Cav1.2 (L-type) channels. Importantly, 30 revealed high metabolic stability on human liver microsomes, negligible hepatotoxicity, and relatively weak inhibition of CYP3A4, CYP2D6, and CYP2C9 isoforms of cytochrome P450, compared to reference compounds. The promising in vivo activity profile and drug-like properties of compound 30 make it an interesting candidate for further preclinical development.

Highlights

Epilepsy remains one of the least understood neurological diseases with complex and multifactorial pathogenesis
The data for the most potent compounds have been bolded for better visualization. a Results showing activity higher than 50% are considered to represent a significant effect of the test compounds; results showing an inhibition between 25% and 50% are indicative of a moderate effect; results showing an inhibition lower than 25% are not considered significant. # Central nervous system (CNS) tetrodotoxin (TTX)-sensitive sodium channels that include Nav1.1, Nav1.2, Nav1.3, and Nav1.6 subtypes
The results of elemental analyses were within ±0.4% of the theoretical values. 1H-NMR and 13C-NMR spectra were obtained in CDCl3 or dimethyl sulfoxide (DMSO)-D6 in a Varian Mercury spectrometer (Varian Inc., Palo Alto, CA, USA), in DMSO-D6 operating at 300 MHz (1H-NMR) and 75 MHz (13C-NMR), or in a JEOL-500 spectrometer

Summary

Introduction

Epilepsy remains one of the least understood neurological diseases with complex and multifactorial pathogenesis. It is estimated that about 50 million people worldwide suffer from this disease, making it the second most common neurological disorder after stroke [1,2]. Despite unquestionable advances in epilepsy research, nearly 30% of patients still experience uncontrolled, debilitating seizures [3]. Several new AEDs such as levetiracetam, brivaracetam, lacosamide, or perampanel have been introduced into the pharmacotherapy of seizures. Despite their efficacy in several types of epilepsy, as well as better tolerance by patients, compared to older AEDs, they have not resolved the problem of drug-resistant epilepsy [5]

Objectives

Methods

Findings

Conclusion