Sussan S, Dagan A, Bialer M
Department of Pharmaceutics, School of Pharmacy, Faculty of Medicine, The Hebrew University of Jerusalem, Israel.
Epilepsy Res. 1999 Jan;33(1):11-21. doi: 10.1016/s0920-1211(98)00076-x.
The objective of this study was to investigate the pharmacokinetics and pharmacodynamics (anticonvulsant activity and neurotoxicity) of a series of amide derivatives of glycinamide in order to explore their structure pharmacokinetic-pharmacodynamic relationship and to discover a glycinamide derivative which might have the potential to become a new antiepileptic agent. The following compounds were investigated: glycylglycine, glycylglycinamide, gaboylglycinamide, N-acetylglycine, N-acetylglycinamide, N-acetylglycylglycinamide, N-acetyl, N'-benzylglycinamide, N-benzyloxycarbonylglycine or Z-glycine, Z-glycinamide, Z-glycylglycine and Z-glycylglycinamide. The anticonvulsant activity and neurotoxicity study was carried out in classical animal models for anticonvulsant screening. The pharmacokinetics of the active compounds was studied in dogs, which is a common animal model for a comparative crossover pharmacokinetic studies. Of the compounds investigated in this study, all the dipeptides of glycinamide and the glycine derivatives were found to be inactive. The only two active compounds were: N-acetyl,N'-benzylglycinamide (VII) and Z-glycinamide (IX). These compounds demonstrated similar pharmacokinetic profiles. Unlike glycine or glycinamide, compounds VII and IX, being lipophilic derivatives of glycinamide, showed anticonvulsant activity in animal models due to their better pharmacodynamic and pharmacokinetic properties. The pharmacodynamics and pharmacokinetics of compounds VII and IX were similar to that of the potential new antiepileptics; N-valproylglycinamide and phthaloylglycinamide. This study provides certain clues concerning the structural requirements for the design of anticonvulsant-active glycine derivatives.
本研究的目的是研究一系列甘氨酰胺酰胺衍生物的药代动力学和药效学（抗惊厥活性和神经毒性），以探索它们的结构-药代动力学-药效学关系，并发现一种可能有潜力成为新型抗癫痫药物的甘氨酰胺衍生物。研究了以下化合物：甘氨酰甘氨酸、甘氨酰甘氨酰胺、γ-氨基丁酰甘氨酰胺、N-乙酰甘氨酸、N-乙酰甘氨酰胺、N-乙酰甘氨酰甘氨酰胺、N-乙酰基、N'-苄基甘氨酰胺、N-苄氧羰基甘氨酸或Z-甘氨酸、Z-甘氨酰胺、Z-甘氨酰甘氨酸和Z-甘氨酰甘氨酰胺。在经典的抗惊厥筛选动物模型中进行了抗惊厥活性和神经毒性研究。在狗身上研究了活性化合物的药代动力学，狗是用于比较交叉药代动力学研究的常见动物模型。在本研究中所研究的化合物中，发现所有甘氨酰胺二肽和甘氨酸衍生物均无活性。仅有的两种活性化合物是：N-乙酰基、N'-苄基甘氨酰胺（VII）和Z-甘氨酰胺（IX）。这些化合物表现出相似的药代动力学特征。与甘氨酸或甘氨酰胺不同，化合物VII和IX作为甘氨酰胺的亲脂性衍生物，由于其更好的药效学和药代动力学性质，在动物模型中显示出抗惊厥活性。化合物VII和IX的药效学和药代动力学与潜在的新型抗癫痫药物N-丙戊酰甘氨酰胺和邻苯二甲酰甘氨酰胺相似。本研究为设计具有抗惊厥活性的甘氨酸衍生物的结构要求提供了一定线索。
