Studies have demonstrated that 2-substituted N-benzyl-2-acetamidoacetamides (2) are potent anticonvulsants. A recent investigation has led to the hypothesis that an important structural feature in 2 for maximal anticonvulsant activity is the placement of a small, substituted heteroatom moiety one atom from the C(2) site. This paper validates this hypothesis. Twelve derivatives of N-benzyl-2-acetamidopropionamide have been prepared in which six different heteroatom substituents (chloro, bromo, iodo, oxygen, nitrogen, and sulfur) were incorporated at the C(3) site. Highly potent activities were observed for the two oxygen-substituted derivatives, N-benzyl-2-acetamido-3-methoxypropionamide (18) and N-benzyl-2-acetamido-3-ethoxypropionamide (19). The ED50 values in mice following intraperitoneal (i.p.) dosing for the maximal electroshock-induced seizure test for 18 and 19 were 8.3 and 17.3 mg/kg, respectively. These values compared favorably to the ED50 value found for phenytoin (ED50 = 6.5 mg/kg). Comparable activities were observed for 18 and 19 upon oral (p.o.) administration to rats (18, ED50 = 3.9 mg/kg; 19, ED50 = 19 mg/kg; phenytoin, ED50 = 23 mg/kg). Evaluation of the individual stereoisomers for 18 demonstrated that the principal anticonvulsant activity resided in the (R)-stereoisomer. The ED50 value for (R)-18 was 4.5 mg/kg, and the ED50 for (S)-18 exceeded 100 mg/kg. This difference in activity for the two stereochemical isomers surpassed comparable values for other members within this class of compounds. The protective indices (PI = TD50/ED50) (where TD50 represents a neurotoxic dose impairing rotorod performance) for (R)-18 in mice (i.p.) and in rats (p.o.) were 6.0 and > 130, respectively.