The structural requirements for the design of antiepileptic-glycine derivatives

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.