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

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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.