Synthesis and anticonvulsant activity of 1-acyl-2-pyrrolidinone derivatives.
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.
Sasaki
H
H
School of Phamaceutical Sciences, Nagasaki University, Japan.
Mori
Y
Y
Nakamura
J
J
Shibasaki
J
J
D000818:Animals; D000927:Anticonvulsants / Q000138:chemical synthesis* / Q000494:pharmacology; D055598:Chemical Phenomena; D002621:Chemistry; D008297:Male; D051379:Mice; D011760:Pyrrolidinones / Q000138:chemical synthesis* / Q000494:pharmacology; D051381:Rats; D011963:Receptors, GABA-A / Q000187:drug effects; D012640:Seizures / Q000188:drug therapy; D012890:Sleep / Q000187:drug effects; D013329:Structure-Activity Relationship; D005680:gamma-Aminobutyric Acid / Q000378:metabolism
D000927:Anticonvulsants; D011760:Pyrrolidinones; D011963:Receptors, GABA-A; D005680:gamma-Aminobutyric Acid