Saito M, Hashimoto M, Kawaguchi N, Fukami H, Tanaka T, Higuchi N
Institute for Fundamental Research, Suntory Research Center, Osaka, Japan.
J Enzyme Inhib. 1990;3(3):163-78. doi: 10.3109/14756369009035834.
Several prolinal derivatives were synthesized and examined for their inhibitory activity on post-proline cleaving enzymes from Flavobacterium meningosepticum and bovine brain and their possible properties as nootropic agents. Almost all the compounds tested inhibited the activity of both enzymes at low IC50 values of the order of nM, but a specificity difference was observed with alkylacyl-prolinal derivatives which strongly inhibited only the bacterial enzyme. Prolyl-prolinal derivatives were the most effective inhibitors for both enzymes. In the passive avoidance test using amnesic rats experimentally induced with scopolamine, the prolinal derivatives that have potent inhibitory activity toward post-proline cleaving enzymes showed also strong anti-amnesic activities at dose of 10-1000 micrograms/kg, i.p. Some of the compounds showed a bell-shape dose dependency. These results suggest that the post-proline cleaving enzymes play an important role in the regulation of learning and memory consolidation in the brain and inhibitors of these enzymes are suggested as possible candidates for nootropic agents, particularly for an anti-amnesic drug.
合成了几种脯氨酸衍生物，并检测了它们对脑膜炎败血黄杆菌和牛脑的脯氨酸裂解酶的抑制活性，以及它们作为促智药的潜在特性。几乎所有测试的化合物在低至纳摩尔级的IC50值时都能抑制这两种酶的活性，但观察到烷基酰基脯氨酸衍生物存在特异性差异，它们仅强烈抑制细菌酶。脯氨酰脯氨酸衍生物是这两种酶最有效的抑制剂。在使用东莨菪碱实验诱导失忆的大鼠进行的被动回避试验中，对脯氨酸裂解酶具有强效抑制活性的脯氨酸衍生物在腹腔注射剂量为10 - 1000微克/千克时也表现出强烈的抗失忆活性。一些化合物呈现出钟形剂量依赖性。这些结果表明，脯氨酸裂解酶在大脑学习和记忆巩固的调节中起重要作用，这些酶的抑制剂被认为可能是促智药的候选物，特别是抗失忆药物。
