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

研究了几种多肽及其衍生物对脯氨酸内肽酶的抑制作用以及作为抗遗忘药物的可能特性。其中，z - thiiopro -thiazolidine、z - thiiopro -prolinal、z - thiiopro - thioproprolinal抑制酶活性的Ki值为nM ~ pM，且这些肽衍生物对脯氨酸内肽酶的作用是特异性的。Z-Thiopro-thioprolinal是体外（Ki=0.005 nM）和体内（1 umol/动物i.p时对大鼠各器官的抑制率为50% ~ 70%）最有效的抑制剂。抑制剂对脑酶活性的影响存在区域差异：中脑最活跃，其次是纹状体、小脑、海马、下丘脑；大脑皮层和延髓也不活跃。在大鼠被动回避学习实验中，z -thiopro - thiiopro -thioprolinal和Z-Pro-prolinal预处理可预防1 μ mol/只、1 μ mol/只东莨菪碱诱导的遗忘，z -thiopro - thiolidine、z - vali -prolinal、Z-Pyr-prolinal和Z-Gly-Pro-CH Cl在训练试验后24和48 h的记忆测试中也有效。这些化合物的抗遗忘作用与体外对脯氨酸内肽酶的抑制作用大致平行。这些结果表明，抑制剂可能通过调节大脑中的酶活性来表现其抗遗忘作用。

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.