para-Substituted N-acetyl-L(S)- and -D(R)-.alpha.-amino-N-phenylglutarimides. A structure-activity study of substituent effects on stereoselective anticonvulsant activity

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Abstract
For purposes of carrying out structure-activity studies on a series of pure R and S enantiomorphs of various p-substituted N-acetyl-.alpha.-amino-N-phenylglutarimides. The p-acetyl, iodo, cyano, ethyl and n-butyl analogs were synthesized. These compounds complimented previous R and S isomers (unsubstituted and the p-chloro, methyl, nitro and methoxyl analogs) synthesized from amino acids of known absolute configuration. The neurotoxic doses (TD50''s), anticonvulsant potencies [maximal electroshock seizures and s.c. metrazole ED50], protective indices (PI = TD50/ED50) and effects on minimal seizure threshold were compared in mice with similar values concomitantly determined for clinically employed anticonvulsants. A parallel relationship was shown between TD50 and ED50 for the R and S analogs. In most cases R isomers had a more rapid onset of action and possessed greater neurotoxicity and greater anticonvulsant potency.