Synthesis and anticonvulsant activity of 1-acyl-2-pyrrolidinone derivatives.

Abstract

Several 1-acyl-2-pyrrolidinone derivatives were synthesized as derivatives of gamma-aminobutyric acid (GABA), and their pharmacological activities and stabilities were investigated. The derivatives showed anticonvulsant effect on picrotoxin-induced seizure at a dose of 200 mg/kg. In particular, 1-decanoyl-2-pyrrolidinone (7) and 1-dodecanoyl-2-pyrrolidinone (8) had a high activity. The anticonvulsant activity showed a dose dependency. Some of 1-acyl-2-pyrrolidinone derivatives prolonged sleeping time which was induced by sodium pentobarbital and showed a recovery from disruption of the memory of passive avoidance response, which was induced by an electroconvulsive shock. As shown by the results of the stability study of 1-acetyl-2-pyrrolidinone (1), it was degraded in an acidic buffer and an alkaline buffer although 2-pyrrolidinone was stable. 1-Acyl-2-pyrrolidinone derivatives were degraded in liver and brain homogenates of mouse and rat. They showed a degradation rate in rat plasma. Conversion of 8 to GABA in mouse liver homogenate was demonstrated. These results suggested that the pharmacological activity of 1-acyl-2-pyrrolidinone is probably due to the release of GABA by hydrolysis of derivatives although further work is necessary.

• Authors: H Sasaki, Y Mori, J Nakamura, J Shibasaki
• Journal: Journal of medicinal chemistry (J Med Chem) Vol. 34 Issue 2 Pg. 628-33 (Feb 1991) ISSN: 0022-2623 [Print] United States
• PMID: 1847429 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Anticonvulsants
• Pyrrolidinones
• Receptors, GABA-A
• gamma-Aminobutyric Acid

Topics

• Animals
• Anticonvulsants (chemical synthesis, pharmacology)
• Chemical Phenomena
• Chemistry
• Male
• Mice
• Pyrrolidinones (chemical synthesis, pharmacology)
• Rats
• Receptors, GABA-A (drug effects)
• Seizures (drug therapy)
• Sleep (drug effects)
• Structure-Activity Relationship
• gamma-Aminobutyric Acid (metabolism)