Preparation and anticonvulsant activity of a series of functionalized alpha-heteroatom-substituted amino acids.
Potent anticonvulsant activity has been reported for (R,S)-2-acetamido-N-benzyl-2-methylacetamide (2a). Select alpha-heteroatom substituted derivatives of 2a have been prepared (26 examples) in which the alpha-methyl group has been replaced by nitrogen (3a-q), oxygen (3r-u), and sulfur (3v-z) containing moieties. The functionalized amino acid derivatives were evaluated in the maximal electroshock seizure (MES) and horizontal screen (tox) tests in mice. The most active compounds were (R,S)-2-acetamido-N-benzyl-2-(methoxyamino)acetamide (31), and (R,S)-2-acetamido-N-benzyl-2-(methoxymethylamino)acetamide (3n). After ip administration, the MES ED50 values for 31 (6.2 mg/kg) and 3n (6.7 mg/kg) compared favorably with phenytoin (9.50 mg/kg).
Kohn
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Department of Chemistry, University of Houston, Texas 77204-5641.
Sawhney
K N
KN
LeGall
P
P
Robertson
D W
DW
Leander
J D
JD
D000081:Acetamides / Q000737:chemistry* / Q000627:therapeutic use; D000596:Amino Acids / Q000737:chemistry*; D000818:Animals; D000927:Anticonvulsants / Q000138:chemical synthesis* / Q000627:therapeutic use; D055598:Chemical Phenomena; D002621:Chemistry; D004597:Electroshock; D008297:Male; D051379:Mice; D015394:Molecular Structure; D009584:Nitrogen; D010100:Oxygen; D012640:Seizures / Q000209:etiology / Q000517:prevention & control; D013329:Structure-Activity Relationship; D013455:Sulfur
D000081:Acetamides; D000596:Amino Acids; D000927:Anticonvulsants; D013455:Sulfur; C070472:2-acetamido-N-benzyl-2-methylacetamide; D009584:Nitrogen; D010100:Oxygen