Glycine, in addition to GABA, is one of the most important neurotransmitter amino acids. The described structure pharmacokinetic pharmacodynamic relationships (SPPR) study explored the possibility of utilizing phthaloyl derivatives of glycine as new antiepileptics. This was carried out by investigating the pharmacokinetics and pharmacodynamics (anticonvulsant activity and neurotoxicity) of the following four phthalimide derivatives: phthaloyl glycine, phthaloyl glycinamide, N,N-diethyl phthaloyl glycinamide and N,N-diisopropyl phthaloyl glycinamide. Phthaloyl glycine did not demonstrate anticonvulsant activity, possibly because of its poor pharmacokinetics, high clearance, low volume of distribution and short half life. The three glycinamide derivatives showed anticonvulsant activity and had better pharmacokinetic profiles, longer half life and mean residence time, than phthaloyl glycine. Phthaloyl glycinamide was more potent than one of the major antiepileptic agents--valproic acid and showed a better margin between activity and neurotoxicity. The four investigated phthaloyl glycine derivatives did not operate as chemical drug delivery systems (CDDS) of glycine, but acted rather as drugs on their own. Phthaloyl glycine was excreted unchanged in the urine while the urinary metabolites of the glycinamide derivatives were phthaloyl glycine and phthaloyl glycinamide. In this analogous series of phthalimide derivatives, minor chemical changes affected dramatically the compounds' pharmacokinetics. The current study demonstrates the benefit of the SPPR approach in developing and selecting a potent antiepileptic compound in intact animals based not only on its intrinsic pharmacodynamic activity, but also on its better pharmacokinetic profile.(ABSTRACT TRUNCATED AT 250 WORDS)