Synthesis and evaluation of anticonvulsant properties of new N-Mannich bases derived from 3-(1-phenylethyl)- and 3-benzyl-pyrrolidine-2, 5-dione. Issue 9 (1st May 2016)

• Record Type: Journal Article
• Authors: Rybka, Sabina; Obniska, Jolanta; Rapacz, Anna; Furgała, Anna; Filipek, Barbara; Żmudzki, Paweł
• Is Part Of: Bioorganic & medicinal chemistry letters. Volume 26:Issue 9(2016)
• Page Start: 2147
• Page End: 2151
• Publication Date: 2016-05-01
• Subjects: Pyrrolidine-2, 5-dione -- Anticonvulsant activity -- In vivo studies; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; 572
• DOI: 10.1016/j.bmcl.2016.03.075
• Languages: English
• ISSNs: 0960-894X

Abstract

Graphical abstract: Abstract: 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 ( sc PTZ) 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 sc PTZ test (ED50 = 39 mg/kg) and in the 6-Hz test (ED50 = 36 mg/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.