title: Synthesis and anticonvulsant properties of new Mannich bases derived from 3-aryl-pyrrolidine-2,5-diones. Part 1.
abstract: A series of new Mannich bases of N-[(4-arylpiperazin-1-yl)-methyl]-3-(chlorophenyl)-pyrrolidine-2,5-diones 10-23 have been synthesized and evaluated for their anticonvulsant activity in maximum electroshock (MES) and subcutaneous pentylenetetrazole (scPTZ) seizure threshold tests. Their neurotoxicity was determined using a rotorod screen. Several molecules showed a promising anticonvulsant profile especially in the MES-test. In this model of seizures, the most active were N-[{4-(4-chlorophenyl)-piperazin-1-yl}-methyl]-3-(3-chlorophenyl)-pyrrolidine-2,5-dione 16 and N-[{4-(3-trifluoromethylphenyl)-piperazin-1-yl}-methyl]-3-(3-chlorophenyl)-pyrrolidine-2,5-dione 17 with ED(50) values of 21.4 mg/kg and 28.83 mg/kg, respectively. Selected derivatives 10, 14, and 16 were tested in the psychomotor seizure 6-Hz test from which N-[{4-(2-chlorophenyl)-piperazin-1-yl}-methyl]-3-(2-chlorophenyl)-pyrrolidine-2,5-dione 10 revealed the highest protection with an ED(50) of 78 mg/kg. Compounds 10, 12, and 17 were also tested in the pilocarpine-induced status PIPS test. Furthermore, 17 was examined in the hippocampal kindling screen after i. p. administration to rats.
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: Maciej
authors.initials: M
authors.lastname: Kopytko
authors.forename: Agnieszka
authors.initials: A
authors.lastname: Zagórska
authors.forename: Iwona
authors.initials: I
authors.lastname: Chlebek
authors.forename: Krzysztof
authors.initials: K
authors.lastname: Kamiński
mesh_terms: D000818:Animals; D000927:Anticonvulsants / Q000009:adverse effects / Q000138:chemical synthesis* / Q000737:chemistry / Q000627:therapeutic use; D004195:Disease Models, Animal; D008297:Male; D008352:Mannich Bases / Q000009:adverse effects / Q000138:chemical synthesis* / Q000737:chemistry / Q000627:therapeutic use; D051379:Mice; D008815:Mice, Inbred Strains; D015394:Molecular Structure; D051381:Rats; D017207:Rats, Sprague-Dawley; D012640:Seizures / Q000188:drug therapy* / Q000209:etiology; D013329:Structure-Activity Relationship; D013388:Succinimides / Q000737:chemistry*
chemical_list: D000927:Anticonvulsants; D008352:Mannich Bases; D013388:Succinimides