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The anticonvulsant activities of N-benzyl 3-methoxypropionamides
S V Andurkar1, J P Stables, H Kohn
1Department of Chemistry, University of Houston, TX 77204-5641, USA.
Abstract:
We recently reported that the ED50 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 (ED50 = 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 (i.p.) (MES ED50 = 79-111 mg/kg). The surprisingly high ED50 values for (R)- and (S)-1 required our redetermining the ED50 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 (i.p.) ED50 > 100, < 300 mg/kg; rat (oral) ED50 = 62 mg/kg). The activities of 3-methoxypropionamides, functionalized amino acids, and related compounds are discussed.
Insights
Stereospecific synthesis revealed that both enantiomers of 2,3-dimethoxypropionamide exhibit similar anticonvulsant activity. Modifications to the C(2) methoxy group showed modest effects, but oral administration of a related compound enhanced activity.
Area of Science:
- Medicinal Chemistry
- Neuropharmacology
- Organic Synthesis
Background:
- The anticonvulsant activity of 2,3-dimethoxypropionamide (1) was previously reported with an ED50 of 30 mg/kg in the maximal electroshock (MES)-induced seizure test in mice.
- Compound 1 shares structural similarities with functionalized amino acids (2), a class of MES-selective anticonvulsant agents known for differential enantiomeric activities.
Purpose of the Study:
- To investigate whether (R)- and (S)-2,3-dimethoxypropionamide enantiomers exhibit differential anticonvulsant activities in the MES-induced seizure test.
- To explore structure-activity relationships (SAR) of compound 1, focusing on the C(2) methoxy group and evaluating oral administration routes.
Main Methods:
- Stereospecific synthesis of (R)- and (S)-2,3-dimethoxypropionamide enantiomers.
- Evaluation of anticonvulsant activity using the MES-induced seizure test in mice (intraperitoneal administration).
- Limited SAR study involving modifications at the C(2) position and testing of a related compound ((R,S)-6) in rats via oral administration.
Main Results:
- Both (R)- and (S)-2,3-dimethoxypropionamide enantiomers displayed nearly equal anticonvulsant activity in mice, with revised ED50 values ranging from 79-111 mg/kg.
- The ED50 for the racemic compound (R,S)-1 was revised to 79 mg/kg.
- Replacement of the C(2) methoxy group resulted in only modest changes in MES activity.
- An enhanced anticonvulsant activity was observed for (R,S)-N-benzyl 2-hydroxy-3-methoxypropionamide ((R,S)-6) upon oral administration to rats (ED50 = 62 mg/kg).
Conclusions:
- Unlike other functionalized amino acids, the enantiomers of 2,3-dimethoxypropionamide do not show differential anticonvulsant activity in the MES test.
- The C(2) methoxy group is not critical for MES anticonvulsant activity.
- Oral administration of modified propionamides can enhance anticonvulsant efficacy, suggesting potential for alternative drug delivery strategies.