Synthesis and evaluation of anticonvulsant properties of new N-Mannich bases derived from 3-(1-phenylethyl)- and 3-benzyl-pyrrolidine-2,5-dione

• Published in: Bioorganic & medicinal chemistry letters 2016-05, Vol.26 (9), p.2147-2151
• Main Authors: Rybka, Sabina, Obniska, Jolanta, Rapacz, Anna, Furgała, Anna, Filipek, Barbara, Żmudzki, Paweł
• Format: Article
• Language: English
• Subjects: Animals; Anticonvulsant activity; Anticonvulsants - chemical synthesis; Anticonvulsants - chemistry; Anticonvulsants - pharmacology; Calcium Channel Blockers - chemical synthesis; Calcium Channel Blockers - chemistry; Calcium Channel Blockers - pharmacology; Calcium Channels, L-Type - metabolism; GABA-A Receptor Antagonists - chemical synthesis; GABA-A Receptor Antagonists - chemistry; GABA-A Receptor Antagonists - pharmacology; In vivo studies; Mannich Bases - chemical synthesis; Mannich Bases - chemistry; Mannich Bases - pharmacology; Mice; Piperazines - chemical synthesis; Piperazines - pharmacology; Pyrrolidine-2,5-dione; Pyrrolidines - chemical synthesis; Pyrrolidines - pharmacology; Receptors, N-Methyl-D-Aspartate - antagonists & inhibitors; Sodium Channel Blockers - chemical synthesis; Sodium Channel Blockers - chemistry; Sodium Channel Blockers - pharmacology; Structure-Activity Relationship; Succinimides - chemical synthesis; Succinimides - chemistry; Succinimides - pharmacology
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2016.03.075

[Display omitted] Two series of new derivatives of pyrrolidine-2,5-dione were synthesized and evaluated for their anticonvulsant properties. Initial screening for their anticonvulsant properties was performed in mice after intraperitoneal administration, using the maximal electroshock (MES), subcutaneous pentylenetetrazole (scPTZ) and 6-Hz seizure tests. Quantitative pharmacological research revealed that the highest level of protection was demonstrated by compound N-[{4-methylpiperazin-1-yl}-methyl]-3-(1-phenylethyl)-pyrrolidine-2,5-dione monohydrochloride (22) which was effective both in the scPTZ test (ED50=39mg/kg) and in the 6-Hz test (ED50=36mg/kg). This molecule showed higher potency than reference antiepileptic drugs such as ethosuximide, lacosamide and valproic acid. With the aim of explaining the possible mechanism of action of the selected molecule, its influence on sodium and calcium channels as well as NMDA and GABAA receptors binding properties were evaluated in vitro.