Synthesis, Anticonvulsant and Antinociceptive Activity of New Hybrid Compounds: Derivatives of 3-(3-Methylthiophen-2-yl)-pyrrolidine-2,5-dione.

Małgorzata Góra,Monika Głuch-Lutwin,Jolanta Obniska,Anna Rapacz,Anna Czopek,Barbara Mordyl,Anna Dziubina

doi:10.3390/ijms21165750

Małgorzata Góra, Monika Głuch-Lutwin + Show 5 more

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https://doi.org/10.3390/ijms21165750

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Abstract

The present study aimed to design and synthesize a new series of hybrid compounds with pyrrolidine-2,5-dione and thiophene rings in the structure as potential anticonvulsant and antinociceptive agents. For this purpose, we obtained a series of new compounds and evaluated their anticonvulsant activity in animal models of epilepsy (maximal electroshock (MES), psychomotor (6 Hz), and subcutaneous pentylenetetrazole (scPTZ) seizure tests). To determine the mechanism of action of the most active anticonvulsant compounds (3, 4, 6, 9), their influence on the voltage-gated sodium and calcium channels as well as GABA transporter (GAT) was assessed. The most promising compound 3-(3-methylthiophen-2-yl)-1-(3-morpholinopropyl)pyrrolidine-2,5-dione hydrochloride (4) showed higher ED50 value than those of the reference drugs: valproic acid (VPA) and ethosuximide (ETX) (62.14 mg/kg vs. 252.7 mg/kg (VPA) in the MES test, and 75.59 mg/kg vs. 130.6 mg/kg (VPA) and 221.7 mg/kg (ETX) in the 6 Hz test, respectively). Moreover, in vitro studies of compound 4 showed moderate but balanced inhibition of the neuronal voltage-sensitive sodium (site 2) and L-type calcium channels. Additionally, the antinociceptive activity of the most active compounds (3, 4, 6, 9) was also evaluated in the hot plate test and writhing tests, and their hepatotoxic properties in HepG2 cells were also investigated. To determine the possible mechanism of the analgesic effect of compounds 3, 6, and 9, the affinity for the TRPV1 receptor was investigated.

Highlights

Epilepsy is a chronic disease of the brain that affects around 50 million people worldwide
It can be concluded that blockage of the neuronal voltage-sensitive sodium and L-type calcium channels could be a possible mechanism of action of compounds 4 and 6
To extend the in vitro characterization of active compounds in antinociceptive in vivo tests, which could define a possible mechanism of action, we studied the effect of compounds 3, 6, and 9 on the TRPV1 receptor

Summary

Introduction

Epilepsy is a chronic disease of the brain that affects around 50 million people worldwide. People with epilepsy have usually more psychological problems such as anxiety or depression and injuries such as fractures and bruising related to seizures. The risk of early death in people with epilepsy is three times higher than that in the general population, with the highest index of premature death in low- and middle-income countries and in rural areas. Up to 70% of people with epilepsy live without seizures with the appropriate use of antiseizure drugs. In the remaining 30% of patients, seizures are not sufficiently controlled; new antiepileptic drugs are still being researched [2]

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