The anticonvulsant activities of N-benzyl 3-methoxypropionamides

We recently reported that the ED(50) value for (R,S)-2,3-dimethoxypropionamide (1) in the maximal electroshock (MES)induced seizure test in mice was 30 mg/kg (Choi, D.; Stables, J.P., Kohn, H. Bioorg. Med. Chem. 1996, 4, 2105). This value is comparable to that observed for phenobarbital (ED(50) = 22 mg/kg). Compound 1 is structurally similar to a class of MES-selective anticonvulsant agents, termed functionalized amino acids (2), that were developed in our laboratory. The distinguishing feature of 2 is the differential activities observed for enantiomers. In this study, we asked whether comparable differences in activities were observed in the MES-induced seizure test for (R)- and (S)-1. We developed stereospecific syntheses for these enantiomers and showed that both compounds exhibit nearly equal anticonvulsant activity in mice (ip) (MES ED(50) = 79-111 mg/kg). The surprisingly high ED(50) values for (R)- and (S)-1 required our redetermining the ED(50) value for (R,S)-1. We revised this value to 79 mg/kg. A limited structure-activity relationship study for 1 was conducted. Special attention was given to the C(2) methoxy unit in 1. We found that replacement of this moiety led to only modest differences in the MES activities upon ip administration to mice. Significantly we observed an enhancement in the anticonvulsant activity for (R,S)-N-benzyl 2-hydroxy-3-methoxypropionamide ((R,S)-6) upon oral administration to rats ((R,S)-6: mice tip) ED(50) > 100, < 300 mg/kg; rat (oral) ED(50) = 62 mg/kg), The activities of 3-methoxypropionamides, functionalized amino acids, and related compounds are discussed. (C) 1999 Elsevier Science Ltd. All rights reserved.