Design, synthesis, and anticonvulsant activity of N-phenylamino derivatives of 3,3-dialkyl-pyrrolidine-2,5-diones and hexahydro-isoindole-1,3-diones

• Published in: Bioorganic & medicinal chemistry 2008-05, Vol.16 (9), p.4921-4931
• Main Authors: Kamiński, Krzysztof, Obniska, Jolanta
• Format: Article
• Language: English
• Subjects: Administration, Oral; Animals; Anticonvulsant activity; Anticonvulsants - chemical synthesis; Anticonvulsants - chemistry; Anticonvulsants - pharmacology; Anticonvulsants. Antiepileptics. Antiparkinson agents; Biological and medical sciences; Dose-Response Relationship, Drug; Drug Design; Drug Evaluation, Preclinical; Electroshock; In vivo studies; Injections, Intraperitoneal; Injections, Subcutaneous; Isoindoles - chemical synthesis; Isoindoles - chemistry; Isoindoles - pharmacology; Male; Medical sciences; Mice; Mice, Inbred Strains; Molecular Structure; Neuropharmacology; Pharmacology. Drug treatments; Pilocarpine - administration & dosage; Pyrrolidine-2,5-diones; Pyrrolidinones - adverse effects; Pyrrolidinones - chemical synthesis; Pyrrolidinones - chemistry; Pyrrolidinones - pharmacology; Rats; Rats, Sprague-Dawley; Seizures - drug therapy; Seizures - prevention & control; Stereoisomerism; Structure-Activity Relationship; Succinimides
• ISSN: 0968-0896; 1464-3391
• DOI: 10.1016/j.bmc.2008.03.037

The majority of compounds investigated showed activity in the MES and scPTZ screens the most widely employed seizure models for early identification of candidate anticonvulsants. 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 69.89 mg/kg in rats. The median toxic dose (TD 50) was 500 mg/kg, providing compound 15 with a protective index (TD 50/ED 50) of 7.15 in the MES test.