title: Synthesis and biological properties of new N-Mannich bases derived from 3-methyl-3-phenyl- and 3,3-dimethyl-succinimides. Part V.
abstract: Twenty four new 1-[(4-phenylpiperazin-1-yl)-methyl]- derivatives of 3-phenyl-3-methyl- (6-17) and 3,3-dimethyl-pyrrolidine-2,5-diones (18-29) have been synthesized and evaluated for their anticonvulsant activity in the maximum electroshock (MES) and subcutaneous pentylenetetrazole (scPTZ) seizure tests after intraperitoneal injection in mice. The acute neurological toxicity was determined using the rotorod screen. Although no anti-seizure properties were found in the scPTZ screen, fourteen compounds revealed protection in electrically induced seizures. From these molecules seven compounds were tested in rats after oral administration (MES test). In the whole series the most effective in rats were 1-[{4-(4-fluorophenyl)-piperazin-1-yl}-methyl]-3-methyl-3-phenyl-pyrrolidine-2,5-dione (8) with ED₅₀ value of 7.78 mg/kg, it's 3-chlorophenyl- (10) and 3,4-dichlorophenyl- (12) analogs with ED₅₀ values of 27.93 mg/kg and 15.11 mg/kg, respectively. To explain the possible mechanism of action for the most active derivatives 8, 10 and 12 the influence on NaV1.2 sodium channel currents were evaluated in vitro. The results of electrophysiological studies showed higher inhibition of NaV1.2 currents in comparison with phenytoin used as a model antiepileptic drug active in electrically induces seizures. Additionally, eleven 3-phenyl-3-methyl-pyrrolidine-2,5-diones as more promising in the anticonvulsant screening were evaluated in the Vibrio harveyi test to estimate their anti/mutagenic activity.
authors.affiliation: Department of Medicinal Chemistry, Faculty of Pharmacy, Jagiellonian University, Medical College, 9 Medyczna Street, 30-688 Cracow, Poland.
authors.forename: Krzysztof
authors.initials: K
authors.lastname: Kamiński
authors.forename: Jolanta
authors.initials: J
authors.lastname: Obniska
authors.forename: Iwona
authors.initials: I
authors.lastname: Chlebek
authors.forename: Piotr
authors.initials: P
authors.lastname: Liana
authors.forename: Elżbieta
authors.initials: E
authors.lastname: Pękala
mesh_terms: D000818:Animals; D000927:Anticonvulsants / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology* / Q000633:toxicity; D060326:Chemistry Techniques, Synthetic; D008297:Male; D008352:Mannich Bases / Q000737:chemistry; D051379:Mice; D016296:Mutagenesis / Q000187:drug effects; D051381:Rats; D012449:Safety; D015222:Sodium Channels / Q000378:metabolism; D013388:Succinimides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology* / Q000633:toxicity; D014733:Vibrio / Q000187:drug effects / Q000235:genetics
chemical_list: D000927:Anticonvulsants; D008352:Mannich Bases; D015222:Sodium Channels; D013388:Succinimides
keywords: 3,3-Disubstituted-pyrrolidine-2,5-diones; Anticonvulsant activity; In vitro studies; In vivo studies; Mannich bases; Sodium channels; Succinimides; Vibrio harveyi assay