title: Design, synthesis, and anticonvulsant activity of N-phenylamino derivatives of 3,3-dialkyl-pyrrolidine-2,5-diones and hexahydro-isoindole-1,3-diones.
abstract: In the present study on the development of new anticonvulsants, the library of differently substituted N-phenylamino pyrrolidine-2,5-dione and hexahydro-isoindole-1,3-dione derivatives was synthesized. The anticonvulsant activity of all the compounds was evaluated using the maximal electroshock (MES) and pentylenetetrazole (scPTZ) screens, which are the most widely employed seizure models for early identification of candidate anticonvulsants. Their neurotoxicity was determined applying the rotorod test. The pharmacological results revealed that the majority of compounds were effective in electrical (MES) and/or pentylenetetrazole induced seizure (scPTZ) models. The quantitative in vivo anticonvulsant evaluation of N-phenylamino-3,3-dimethyl-pyrrolidine-2,5-dione (15), conducted at the time of peak pharmacodynamic activity (TPE), showed the MES ED(50) value of 69.89mg/kg in rats. The median toxic dose (TD(50)) was 500mg/kg, providing compound 15 with a protective index (TD(50)/ED(50)) of 7.15 in the MES test.
authors: Department of Medicinal Chemistry, Jagiellonian University, Medical College, 9 Medyczna Street, 30-688 Kraków, Poland. kaminskik@cm-uj.krakow.pl
authors: Krzysztof
authors: K
authors: Kamiński
authors: Jolanta
authors: J
authors: Obniska
mesh_terms: D000284:Administration, Oral; D000818:Animals; D000927:Anticonvulsants / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D004353:Drug Evaluation, Preclinical; D004597:Electroshock; D007274:Injections, Intraperitoneal; D007279:Injections, Subcutaneous; D054833:Isoindoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D015394:Molecular Structure; D010862:Pilocarpine / Q000008:administration & dosage; D011760:Pyrrolidinones / Q000009:adverse effects / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D012640:Seizures / Q000188:drug therapy* / Q000517:prevention & control; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
chemical_list: D000927:Anticonvulsants; D054833:Isoindoles; D011760:Pyrrolidinones; D010862:Pilocarpine