Synthesis and anticonvulsant activity of N,N-phthaloyl derivatives of central nervous system inhibitory amino acids.
In order to study the influence of the length of the amino acid chain of N,N-phthaloyl-amino acid amides as analogues of the former anticonvulsant taltrimide on the seizure-antagonizing activity glycine, beta-alanine and gamma-aminobutyric acid (GABA) derivatives were synthesized. The corresponding taurine derivatives were also included. Generally, the glycine-derived amides showed a higher activity than the beta-alanine and GABA derivatives in the maximal electroshock seizure (MES) test in mice upon intraperitoneal administration. The activity was comparable to the respective taurine derivatives. The N,N-phthaloyl-glycine amides were also active in the MES test upon oral administration to rats. No significant activity was noted in the seizure threshold test with subcutaneous pentylene-tetrazole. The ED50 of N,N-phthaloyl-glycine ethyl amide (4b) in the MES test upon intraperitoneal administration to mice was 19.1 mg/kg. On a molar basis this activity is comparable to the activity of phenytoin with little toxicity in the rotorod test. In conclusion, N,N-phthaloyl-glycine amides might represent promising antiepileptic drugs.
Usifoh
C O
CO
Department of Pharmaceutical Chemistry, University of Jena, Philosophenweg 14, 07743 Jena, Germany.
Lambert
D M
DM
Wouters
J
J
Scriba
G K
GK
D000596:Amino Acids / Q000138:chemical synthesis* / Q000494:pharmacology*; D000818:Animals; D000927:Anticonvulsants / Q000138:chemical synthesis* / Q000494:pharmacology*; D055598:Chemical Phenomena; D002627:Chemistry, Physical; D003292:Convulsants / Q000494:pharmacology; D004597:Electroshock; D007202:Indicators and Reagents; D051379:Mice; D010433:Pentylenetetrazole / Q000037:antagonists & inhibitors / Q000494:pharmacology; D010795:Phthalic Acids / Q000138:chemical synthesis* / Q000494:pharmacology*; D013329:Structure-Activity Relationship
D000596:Amino Acids; D000927:Anticonvulsants; D003292:Convulsants; D007202:Indicators and Reagents; D010795:Phthalic Acids; D010433:Pentylenetetrazole