The structural requirements for the design of antiepileptic-glycine derivatives.
Glycine is a major inhibitory neurotransmitter and recent reports have shown that certain lipophilic derivatives of glycine demonstrate anticonvulsant activity in intact animals. In these studies, glycinamide derivatives were found to be more potent than their corresponding glycine analogues. Consequently, the objective of the current study was to investigate the pharmacokinetics and pharmacodynamics (anticonvulsant activity and neurotoxicity) of the following phenyl derivatives of glycinamide: N'-benzyl glycinamide, N-benzyloxycarbonyl glycinamide (Z-glycinamide), Z-glycine, N-Z,N'-benzyl glycinamide and N-phenylacetyl glycinamide. The antiepileptic activity and neurotoxicity was carried out in classical animal models for antiepileptic screening. The pharmacokinetics of the active compounds were studied in dogs, a common animal model for comparative crossover pharmacokinetic studies. Of the compounds investigated in this study, Z-glycinamide, N'-benzyl glycinamide and N-Z,N'-benzyl glycinamide were found to be active. Therefore, the disposition of Z-glycinamide and N-Z,N'-benzyl glycinamide in comparison to Z-glycine was studied in plasma, brain, liver and urine of rats. The disposition of Z-glycinamide and N-Z,N'-benzyl glycinamide into the brain was better than that of Z-glycine. Unlike glycine or glycinamide, Z-glycinamide and N-Z,N'-benzyl glycinamide showed antiepileptic activity in animal models due to their better pharmacodynamic and pharmacokinetic properties. The pharmacokinetics of Z-glycinamide was similar in dogs and rats. Substitution of the Z group with the analogous phenylacetyl moiety led to inactive compounds. In an analogous series of compounds, the loss of the anticonvulsant activity may be due to pharmacodynamic and pharmacokinetic reasons. This study provides certain clues concerning the structural requirements for the design of antiepileptic-active glycine derivatives.
Sussan
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S
Department of Pharmaceutics, School of Pharmacy, Faculty of Medicine, The Hebrew University of Jerusalem, Israel.
Dagan
A
A
Blotnik
S
S
Bialer
M
M
D000818:Animals; D000927:Anticonvulsants / Q000097:blood / Q000737:chemistry* / Q000493:pharmacokinetics / Q000652:urine; D001921:Brain / Q000378:metabolism; D002851:Chromatography, High Pressure Liquid; D004285:Dogs; D015195:Drug Design; D005998:Glycine / Q000031:analogs & derivatives* / Q000737:chemistry*; D008099:Liver / Q000378:metabolism; D008297:Male; D051381:Rats; D011919:Rats, Inbred Strains
D000927:Anticonvulsants; D005998:Glycine