The anticonvulsant activities of functionalized N-benzyl 2-acetamidoacetamides. The importance of the 2-acetamido substituent.
Recent studies have demonstrated that substituted N-benzyl 2-acetamidoacetamides provide significant protection against maximal electroshock (MES)-induced seizures in mice and rats. In this study, we investigated whether the 2-acetamido moiety was necessary for anticonvulsant activity. Ten derivatives of the known anticonvulsant, N-benzyl 2-acetamido-2-phenyl-acetamide were prepared in which the 2-acetamido group was replaced by hydrogen, methyl, oxygen, and halogen substituents. Evaluation of these compounds in the MES-induced seizure test demonstrated that both the hydroxy and the methexy compounds provided full protection against MES-induced seizures in mice given ip at 100 mg/kg. Moreover, evaluation of the individual stereoisomers for the hydroxy compound showed that the principal activity resided in the (R)-isomer. These findings demonstrated that the 2-acetamido substituent is important but not obligatory for the prevention of MES-induced seizures. Further supporting evidence was provided by comparing the pharmacological activities of N-benzyl 2,3-dimethoxypropionamide with N-benzyl 2-acetamido-3-methoxypropionamide. The ED50 value for the former in the MES test was 30 mg/kg (i.p.), which compared favorably with phenobarbital (ED50 = 22 mg/kg), but the ED50 value for N-benzyl 2-acetamido-3-methoxypropionamide was 8.3 mg/kg.
Choi
D
D
Department of Chemistry, University of Houston, TX 77204-5641, USA.
Stables
J P
JP
Kohn
H
H
D000081:Acetamides / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D000818:Animals; D000927:Anticonvulsants / Q000737:chemistry* / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D051379:Mice; D015394:Molecular Structure; D013329:Structure-Activity Relationship
D000081:Acetamides; D000927:Anticonvulsants