The effect of N-substituted alkyl groups on anticonvulsant activities of N-Cbz-alpha-amino-N-alkylglutarimides.

In order to examine the effects of N-substituted alkyl group on the anticonvulsant activities of N-Cbz-alpha-aminoglutarimides as novel anticonvulsants with broad spectrum, a series of (R) or (S) N-Cbz-alpha-amino-N-alkylglutarimides (1 and 2) were prepared from the corresponding (R) or (S) N-Cbz-glutamic acid and evaluated for the anticonvulsant activities in the maximal electroshock seizure (MES) test and pentylenetetrazol induced seizure (PTZ) test, including the neurotoxicity. The most potent compound in the MES test was (S) N-Cbz-alpha-amino-N-methylglutarimide (ED50=36.3 mg/kg, PI=1.7). This compound was also most potent in the PTZ test (ED50=12.5 mg/kg, PI=5.0). The order of anticonvulsant activities against the MES test as evaluated from ED50 values for (R) series was N-methyl > N-H > N-ethyl > N-allyl; for the (S) series N-methyl > N-H > N-ethyl > N-allyl > N-isobutyl compound. Against the PTZ tests, the order of anticonvulsant activities showed similar pattern; for the (R) series, N-methyl > N-H > N-ethyl > N-allyl; for the (S) series N-methyl > N-H > N-ethyl > N-allyl > N-isobutyl compound. From the above results, N-substituted alkyl groups were thought to play an important role for the anticonvulsant activities of N-Cbz-alpha-amino-N-alkylglutarimides.