Synthesis, Anticonvulsant, and Antinociceptive Activity of New 3-(2-Chlorophenyl)- and 3-(3-Chlorophenyl)-2,5-dioxo-pyrrolidin-1-yl-acetamides

• Main Authors: Małgorzata Góra, Anna Czopek, Anna Rapacz, Anna Gębska, Katarzyna Wójcik-Pszczoła, Elżbieta Pękala, Krzysztof Kamiński
• Format: Article
• Language: English
• Published: MDPI AG 2021-03-01
• Series: Molecules
• Subjects: anticonvulsant activity; antinociceptive activity; pyrrolidine-2,5-dione; amides
• Online Access: https://www.mdpi.com/1420-3049/26/6/1564

The new series of 3-(2-chlorophenyl)- and 3-(3-chlorophenyl)-pyrrolidine-2,5-dione-acetamide derivatives as potential anticonvulsant and analgesic agents was synthesized. The compounds obtained were evaluated in the following acute models of epilepsy: maximal electroshock (MES), psychomotor (6 Hz, 32 mA), and subcutaneous pentylenetetrazole (<i>sc</i>PTZ) seizure tests. The most active substance-3-(2-chlorophenyl)-1-{2-[4-(4-fluorophenyl)piperazin-1-yl]-2-oxoethyl}-pyrrolidine-2,5-dione (<b>6</b>) showed more beneficial ED₅₀ and protective index values than the reference drug—valproic acid (68.30 mg/kg vs. 252.74 mg/kg in the MES test and 28.20 mg/kg vs. 130.64 mg/kg in the 6 Hz (32 mA) test, respectively). Since anticonvulsant drugs are often effective in neuropathic pain management, the antinociceptive activity for two the promising compounds—namely, <b>6</b> and <b>19</b>—was also investigated in the formalin model of tonic pain. Additionally, for the aforementioned compounds, the affinity for the voltage-gated sodium and calcium channels, as well as GABA_A and TRPV1 receptors, was determined. As a result, the most probable molecular mechanism of action for the most active compound <b>6</b> relies on interaction with neuronal voltage-sensitive sodium (site 2) and L-type calcium channels. Compounds <b>6</b> and <b>19</b> were also tested for their neurotoxic and hepatotoxic properties and showed no significant cytotoxic effect.