Para-substituted N-acetyl-L(S)- and -D(R)-alpha-amino-N-phenylglutarimides. A structure-activity study of substituent effects on steroselective anticonvulsant activity.
For purposes of carrying out structure-activity studies on a series of pure R and S enantiomorphs of various para-substituted N-acetyl-alpha-amino-N-phenylglutarimides, we synthesized the p-acetyl, iodo, cyano, ethyl, and n-butyl analogues. These compounds complimented previous R and S isomers (unsubstituted and the p-chloro, methyl, nitro, and methoxyl analogues) synthesized in our laboratories from amino acids of known absolute configuration. The neurotoxic doses (TD50's), anticonvulsant potencies [maximal electroshock seizures (MES) and subcutaneous metrazole (sc Met) ED50's], protective indices (PI = TD50/ED50), and effects on minimal seizure threshold (iv Met) were compared with similar values concomitantly determined for clinically employed anticonvulsants. A parallel relationship was shown between neutotoxicity (TD50) and potency (ED50) for the R and S analogues. In most cases R isomers had a more rapid onset of action and possessed greater neurotoxicity and greater anticonvulsant potency.
D000818:Animals; D000927:Anticonvulsants / Q000138:chemical synthesis* / Q000627:therapeutic use / Q000633:toxicity; D005013:Ethosuximide / Q000627:therapeutic use; D008297:Male; D051379:Mice; D010672:Phenytoin / Q000627:therapeutic use; D010880:Piperidines / Q000138:chemical synthesis*; D010881:Piperidones / Q000138:chemical synthesis* / Q000627:therapeutic use / Q000633:toxicity; D012640:Seizures / Q000517:prevention & control; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D014293:Trimethadione / Q000627:therapeutic use
D000927:Anticonvulsants; D010880:Piperidines; D010881:Piperidones; D005013:Ethosuximide; D010672:Phenytoin; C007864:glutarimide; D014293:Trimethadione