Glycine is a major inhibitory neurotransmitter and recent reports have show
n 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. Conseq
uently, the objective of the current study was to investigate the pharmacok
inetics 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 gly
cinamide and N-phenylacetyl glycinamide. The antiepileptic activity and neu
rotoxicity was carried out in classical animal models for antiepileptic scr
eening. 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 glycina
mide 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 dispo
sition of Z-glycinamide and N-Z,N'-benzyl glycinamide into the brain was be
tter than that of Z-glycine. Unlike glycine or glycinamide, Z-glycinamide a
nd N-Z,N'-benzyl glycinamide showed antiepileptic activity in animal models
due to their better pharmacodynamic and pharmacokinetic properties. The ph
armacokinetics of Z-glycinamide was similar in dogs and rats. Substitution
of the Z group with the analogous phenylacetyl moiety led to inactive compo
unds. In an analogous series of compounds, the loss of the anticonvulsant a
ctivity may be due to pharmacodynamic and pharmacokinetic reasons. This stu
dy provides certain clues concerning the structural requirements for the de
sign of antiepileptic-active glycine derivatives. (C) 1999 Elsevier Science
B.V. All rights reserved.