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Studies on the anti-amnesic effect of specific inhibitors for prolyl endopeptidase.

脯氨酰内肽酶特异性抑制剂抗遗忘作用的研究。

基本信息

批准号：
61571054
负责人：
YOSHIMOTO Tadashi
金额：
$ 1.15万
依托单位：
Nagasaki University, School of Pharmaceutical Sciences
依托单位国家：
日本
项目类别：
Grant-in-Aid for General Scientific Research (C)
财政年份：
1986
资助国家：
日本
起止时间：
1986 至 1987
项目状态：
已结题

项目摘要

Several peptides and peptide derivatives were tested for their inhibitory effect on prolyl endopeptidase and possible properties as anti-amnesic agents. Among the compounds tested, Z-Thiopro-thiazolidine, Z-Thiopro-prolinal, Z-Thiopro-thioprolinal inhibited the enzyme activities at Ki values in the order of nM to pM, and the effect of these peptide derivatives was specific for prolyl endopeptidase. Z-Thiopro-thioprolinal was the most effective inhibitor in vitro (Ki=0.005 nM) and in vivo (50 to 70 % inhibition in various organs of rat at a dose of 1 umol/animal i.p.). Regional differences were observed in the effect of inhibitors on the brain enzyme activities: most active in mesencephalon, followed by striatum, cerebellum, hippocampus, hypothalamus; and inactive in cerebral cortex and medulla oblongata. In the passive avoidance learning test using rats, pretreatment with Z-Thiopro-thioprolinal and Z-Pro-prolinal prevented the induction of amnesia by scopolamine at the dose of 1 umol/animal, i.p. Z-Thiopro-thiazolidine, Z-Val-prolinal, Z-Pyr-prolinal and Z-Gly-Pro-CH Cl were also effective in the retention test at 24 and 48 h after the training trial. The anti-amnesic effect of these compounds was approximately parallel to the in vitro inhibitory activities on prolyl endopeptidase. These results suggest the possibility that the inhibitors exhibit their anti-amnesic effect through the regulation of the enzyme activity in the brain.

测试了几种多肽和多肽衍生物对Pro-内肽酶的抑制作用以及作为抗健忘剂的可能性质。在所研究的化合物中，Z-硫代-噻唑烷、Z-硫代-脯氨醛、Z-硫代-硫代脯氨醛对KI值的抑制作用从Nm到Pm依次递减，且这些多肽衍生物对Pro-内肽酶的作用是专一性的。在体外(Ki=0.005 nM)和体内(1umol/只动物ip，对大鼠各器官的抑制率为50%~70%)，Z-硫代丙氨醛是最有效的抑制剂。抑制物对脑酶活性的影响存在地区差异：中脑活性最高，纹状体、小脑、海马体、下丘脑次之，大脑皮层和延髓不活性。在大鼠被动回避学习实验中，预先给予Z-硫代-硫代-脯氨酸和Z-Pro-Pro可阻止东莨菪碱1umol/只，ip。在训练后24小时和48小时，Z-噻吩噻唑烷、Z-Val-Pro-Prolinal、Z-Py-Pro-Prolinal和Z-Gly-Pro-CH Cl也是有效的。这些化合物的抗记忆作用与体外对脯氨酰内肽酶的抑制作用基本平行。这些结果表明，这些抑制剂可能是通过调节大脑中的酶活性来发挥抗记忆作用的。