title: Synthesis and anticonvulsant properties of new N-Mannich bases derived from 3,3-diphenyl- and 3-ethyl-3-methyl-pyrrolidine-2,5-diones. Part III.
abstract: Twenty-four new N-[(4-phenylpiperazin-1-yl)-methyl] derivatives of 3,3-diphenyl- (7-18) and 3-ethyl-3-methyl-pyrrolidine-2,5-dione (19-30) were synthesized and evaluated for their anticonvulsant activity in the maximum electroshock (MES) and subcutaneous pentylenetetrazole (scPTZ) seizure tests. The acute neurological toxicity was determined using the rotorod screen. Eleven compounds were active and revealed protection only in electrically induced seizures (MES). In the whole series the most effective compound was N-[{4-(3-trifluoromethylphenyl)-piperazin-1-yl}-methyl]-3,3-diphenyl-pyrrolidine-2,5-dione (14) with an ED(50)  value of 30.3 mg/kg (p.o. rats) in the MES test. To explain the possible mechanism of action, for chosen active derivatives 7, 8, 9, 11, 14, 23, and 26, their influence on Na(V) 1.2 sodium channel currents was evaluated in vitro. The crystallographic structures for several molecules (8, 10, and 11) were solved.
authors.affiliation: Department of Medicinal Chemistry, Jagiellonian University, Medical College, Kraków, Poland. mfobnisk@cyf-kr.edu.pl
authors.forename: Jolanta
authors.initials: J
authors.lastname: Obniska
authors.forename: Iwona
authors.initials: I
authors.lastname: Chlebek
authors.forename: Krzysztof
authors.initials: K
authors.lastname: Kamiński
authors.forename: Janina
authors.initials: J
authors.lastname: Karolak-Wojciechowska
mesh_terms: D000818:Animals; D000927:Anticonvulsants / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D018360:Crystallography, X-Ray; D004195:Disease Models, Animal; D008297:Male; D008352:Mannich Bases / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D051379:Mice; D062551:NAV1.2 Voltage-Gated Sodium Channel / Q000187:drug effects / Q000378:metabolism; D010433:Pentylenetetrazole / Q000633:toxicity; D051381:Rats; D017207:Rats, Sprague-Dawley; D012640:Seizures / Q000188:drug therapy*; D013329:Structure-Activity Relationship; D013388:Succinimides / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D023382:Toxicity Tests, Acute
chemical_list: D000927:Anticonvulsants; D008352:Mannich Bases; D062551:NAV1.2 Voltage-Gated Sodium Channel; D013388:Succinimides; D010433:Pentylenetetrazole