Pharmacokinetic analysis and anticonvulsant activity of glycine and glycinamide derivatives

Sherbel Sussan, Arie Dagan, Meir Bialer*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

11 Scopus citations

Abstract

The objective of this study was to investigate the pharmacokinetics and pharmacodynamics (anticonvulsant activity and neurotoxicity) of a series of amide derivatives of glycinamide in order to explore their structure pharmacokinetic-pharmacodynamic relationship and to discover a glycinamide derivative which might have the potential to become a new antiepileptic agent. The following compounds were investigated: glycylglycine, glycylglycinamide, gaboylglycinamide, N-acetylglycine, N-acetylglycinamide, N-acetylglycylglycinamide, N-acetyl, N'-benzylglycinamide, N- benzyloxycarbonylglycine or Z-glycine, Z-glycinamide, Z-glycylglycine and Z- glycylglycinamide. The anticonvulsant activity and neurotoxicity study was carried out in classical animal models for anticonvulsant screening. The pharmacokinetics of the active compounds was studied in dogs, which is a common animal model for a comparative crossover pharmacokinetic studies. Of the compounds investigated in this study, all the dipeptides of glycinamide and the glycine derivatives were found to be inactive. The only two active compounds were: N-acetyl,N'-benzylglycinamide (VII) and Z-glycinamide (IX). These compounds demonstrated similar pharmacokinetic profiles. Unlike glycine or glycinamide, compounds VII and IX, being lipophilic derivatives of glycinamide, showed anticonvulsant activity in animal models due to their better pharmacodynamic and pharmacokinetic properties. The pharmacodynamics and pharmacokinetics of compounds VII and IX were similar to that of the potential new antiepileptics; N-valproylglycinamide and phthaloylglycinamide. This study provides certain clues concerning the structural requirements for the design of anticonvulsant-active glycine derivatives.

Original languageEnglish
Pages (from-to)11-21
Number of pages11
JournalEpilepsy Research
Volume33
Issue number1
DOIs
StatePublished - 1 Jan 1999

Keywords

  • Anticonvulsant activity
  • Glycinamide derivatives
  • Glycine
  • New antiepileptics
  • Pharmacokinetics

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