title: Preparation and anticonvulsant activity of a series of functionalized alpha-aromatic and alpha-heteroaromatic amino acids.
abstract: We recently reported the potent anticonvulsant activity of (R,S)-alpha-acetamido-N-benzyl-alpha-phenylacetamide (2b). Selectively substituted derivatives of this compound have now been prepared (23 examples) and evaluated in the maximal electroshock seizure (MES) and horizontal screen (tox) tests in mice. In several key cases, replacement of the alpha-phenyl substituent in 2b by a relatively small, electron-rich, heteroaromatic moiety led to a substantial improvement in the anticonvulsant potency of the drug candidate. The most active compounds were (R,S)-alpha-acetamido-N-benzyl-2-furanacetamide (2g) and (R,S)-alpha-acetamido-N-benzyl-2-pyrroleacetamide (2i). After ip administration, the MES ED50 values for 2g (10.3 mg/kg) and 2i (16.1 mg/kg) compared well with phenytoin (9.50 mg/kg). Evaluation of the two individual enantiomers of 2g demonstrated that the anticonvulsant activity resided in the R stereoisomer. The low ED50 value (3.3 mg/kg) for (R)-2g contributed to the large protective index (TD50/ED50) observed for this drug candidate, which approached that of phenytoin.
authors.affiliation: Department of Chemistry, University of Houston, Texas 77204-5641.
authors.forename: H
authors.initials: H
authors.lastname: Kohn
authors.forename: K N
authors.initials: KN
authors.lastname: Sawhney
authors.forename: P
authors.initials: P
authors.lastname: LeGall
authors.forename: J D
authors.initials: JD
authors.lastname: Conley
authors.forename: D W
authors.initials: DW
authors.lastname: Robertson
authors.forename: J D
authors.initials: JD
authors.lastname: Leander
mesh_terms: D000596:Amino Acids / Q000138:chemical synthesis / Q000494:pharmacology; D000818:Animals; D000927:Anticonvulsants / Q000138:chemical synthesis* / Q000494:pharmacology; D008297:Male; D051379:Mice; D013329:Structure-Activity Relationship
chemical_list: D000596:Amino Acids; D000927:Anticonvulsants