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

测试了几种肽和肽衍生物对脯氨酰内肽酶的抑制作用和作为抗遗忘剂的可能性质。在所测试的化合物中，Z-硫代噻唑烷、Z-硫代脯氨醛、Z-硫代脯氨醛在nM至pM的Ki值下抑制酶活性，并且这些肽衍生物的作用对脯氨酰内肽酶是特异性的。在体外（Ki=0.005 nM）和体内（在1 umol/动物i. p.剂量下，大鼠各器官中的抑制率为50 - 70%），Z-硫普罗-硫脯氨酸是最有效的抑制剂。抑制剂对脑内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，大脑皮质和延髓不活跃。在大鼠被动回避学习实验中，预先给予Z-硫普罗脯氨酸和Z-脯脯氨酸可防止东莨菪碱以1 μ mol/只的剂量诱导的遗忘。在训练试验后24和48 h，腹腔注射Z-硫普罗噻唑烷、Z-Val-脯氨酸、Z-Pyr-脯氨酸和Z-Gly-Pro-CH Cl在保持试验中也有效。这些化合物的抗遗忘作用与其对脯氨酰内肽酶的体外抑制活性大致平行。这些结果表明，抑制剂通过调节大脑中的酶活性来表现出其抗遗忘作用的可能性。

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.