Synthesis and anticonvulsant evaluation of A series of (R)- and (S)-N-Cbz-α-aminosuccinmide and their structure activity relationship

Abstract

A series ofN-Cbz-α-aminosucinimides (1), combining common moieties of various anticonvulsants such as N-CO-C-N and cyclic imide in a single molecule, were synthesized from the corresponding (R)- and (S)-N-Cbz-aspartic acid (2). And theirin vivo anticonvulsant evaluations in MES and PTZ test were investigated. And also the rotorod test for neurotoxicity was investigated. All the tested compounds (1), except1c and1f, showed significant anticonvulsant activities in both MES and PTZ test. And the most active compound among them in MES test was (R)-N-Cbz-α-amino-N-methylsuccinimide (1b) (ED50=52.5 mg/kg) and (S)-N-Cbz-aminosuccinimide((1d) was most active in PTZ test (ED50=78.1 mg/kg). And the TD50 values of the tested compounds were above 117.5 mg/kg. These pharmacological data were comparable to those of currently available anticonvulsants. And also we found that the pharmacological effects were dependent on theirN-substituted alkyl chains and their stereochemistry.