Anticonvulsant activity and neurotoxicity of the enantiomers of DL-HEPP

DL-3-hydroxy-3-phenylpentanamide (DL-HEPP) is an anticonvulsant with a broad profile of activity. In order to study if there exists differences in biological activity between its enantiomers, we resolved the racemate from the (-) brucine and (-) 1-phenylethylamine salts of the acids. The optically active acids were then esterified with diazomethane and reacted with ammonia to give (+)-3-hydroxy-3-phenylpentanamide ((+)-HEPP) and (-)-HEPP. The enantiomeric purity of the amides was determined using proton magnetic resonance in the presence of europium tris-[3-(trifluoromethylhydroxymethylene)-(+)camphorate] and chiral high performance liquid chromatography. Optical purity of the amides was greater than 99% enantiomeric excess, impurities were not detected. Pharmacologically, DL-HEPP and its enantiomers have a similar significant anticonvulsant activity at peak drug effect against pentylenetetrazol-induced seizures, but a variation in time between the enantiomers was found with the anticonvulsant activity. In the rotarod ataxia test, the neurotoxicity of the enantiomers of DL-HEPP was also similar. The therapeutic indices of DL-HEPP and its enantiomers against the seizures induced by pentylenetrazol were better than valproate, an antiepileptic widely used in clinics.   Key words: Anticonvulsants, DL-3-hydroxy-3-phenylpentanamide enantiomers, DL-HEPP, resolution, (-) HEPP, (+) HEPP, valproate.