Sasaki H, Mori Y, Nakamura J, Shibasaki J
School of Phamaceutical Sciences, Nagasaki University, Japan.
J Med Chem. 1991 Feb;34(2):628-33. doi: 10.1021/jm00106a025.
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.
合成了几种1-酰基-2-吡咯烷酮衍生物作为γ-氨基丁酸（GABA）的衍生物，并研究了它们的药理活性和稳定性。这些衍生物在剂量为200mg/kg时对印防己毒素诱导的惊厥有抗惊厥作用。特别是，1-癸酰基-2-吡咯烷酮（7）和1-十二酰基-2-吡咯烷酮（8）具有高活性。抗惊厥活性呈剂量依赖性。一些1-酰基-2-吡咯烷酮衍生物延长了戊巴比妥钠诱导的睡眠时间，并显示出从电惊厥休克诱导的被动回避反应记忆破坏中恢复。如1-乙酰基-2-吡咯烷酮（1）的稳定性研究结果所示，尽管2-吡咯烷酮稳定，但它在酸性缓冲液和碱性缓冲液中都会降解。1-酰基-2-吡咯烷酮衍生物在小鼠和大鼠的肝脏和脑匀浆中会降解。它们在大鼠血浆中显示出降解率。在小鼠肝脏匀浆中证实了8向GABA的转化。这些结果表明，1-酰基-2-吡咯烷酮的药理活性可能是由于衍生物水解释放GABA所致，尽管还需要进一步的研究。
