Anticonvulsant and neurotoxicological properties of 4-amino- N-(2-ethylphenyl)benzamide, a potent ameltolide analogue

• Published in: Biomedicine & pharmacotherapy 1997, Vol.51 (3), p.131-136
• Main Authors: Diouf, O, Bourhim, M, Lambert, D.M., Poupaert, J.H., Stables, J.P., Vamecq, J
• Format: Article
• Language: English
• Subjects: 4-amino- N-(2-ethylphenyl)benzamide; 4-aminobenzamide pharmacophore; Administration, Oral; ameltolide; Animals; anticonvulsant activity; Anticonvulsants - administration & dosage; Anticonvulsants - pharmacology; Anticonvulsants. Antiepileptics. Antiparkinson agents; antiepileptic drug; Benzamides - administration & dosage; Benzamides - chemistry; Benzamides - pharmacology; Biological and medical sciences; Convulsants - pharmacology; Dose-Response Relationship, Drug; Electroshock; Injections, Intraperitoneal; Male; Medical sciences; Mice; Mice, Inbred Strains; Nervous System - drug effects; Neuropharmacology; neurotoxicity; Pentylenetetrazole - pharmacology; Pharmacology. Drug treatments; phenytoin; Phenytoin - administration & dosage; Phenytoin - chemistry; Phenytoin - pharmacology; Rats; Rats, Sprague-Dawley; Seizures - etiology
• ISSN: 0753-3322; 1950-6007
• DOI: 10.1016/S0753-3322(97)86911-9

A well documented study on the anticonvulsant properties of 4-amino- N-(2-ethylphenyl)benzamide (4-AEPB) is here provided. Initial screening in mice dosed intraperitoneally and rats dosed orally indicated that 4-AEPB is active against maximal electroshock—induced seizures (MES), but does not protect animals against subcutaneous pentylenetetrazole (sc Ptz)-induced seizures. Quantitative evaluation of anti-MES activity and neurotoxicity of 4-AEPB given intraperitoneally to mice provided ED 50 and TD 50 values amounting to 28.6 and 96.3 μmol/kg respectively, resulting in a protective index (PI = TD 50/ED 50) equal to 3.36. Further quantitative evaluation in rats dosed orally indicated that the respective ED 50 and TD 50 values for 4-AEPB were 29.8 and more than 1,530 μmol/kg, resulting in a very high PI value of over 51. Comparison of anticonvulsant properties and neurotoxicity of 4-AEPB with those previously reported in the literature for two 4-aminobenzamide derivatives, 4-amino- N-(2,6-dimethylphenyl)benzamide (or ameltolide, an antiepileptic drug prototype developed by Eli Lilly), and phenytoin, underlines the value of 4-AEPB for future pharmacological development. In this perspective, an additional favorable element is represented by the ability of 4-AEPB to increase the seizure threshold in the intravenous Ptz seizure threshold test in mice dosed intraperitoneally. Molecular modeling studies show that the translocation of one carbon unit in the isomerization of the 2,6-dimethylphenyl moiety of ameltolide to the 2-ethylphenyl counterpart succeeds in maintaining the conformational low energy presentation adopted by ameltolide, providing clues as to why the 4-AEPB here described is an anticonvulsant agent derived from the 4-aminobenzamide pharmacophore platform as potent as ameltolide.