title: Synthesis and inhibitory activity of acyl-peptidyl-prolinalderivatives toward post-proline cleaving enzyme as nootropic agents.
abstract: 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.
authors.affiliation: Institute for Fundamental Research, Suntory Research Center, Osaka, Japan.
authors.forename: M
authors.initials: M
authors.lastname: Saito
authors.forename: M
authors.initials: M
authors.lastname: Hashimoto
authors.forename: N
authors.initials: N
authors.lastname: Kawaguchi
authors.forename: H
authors.initials: H
authors.lastname: Fukami
authors.forename: T
authors.initials: T
authors.lastname: Tanaka
authors.forename: N
authors.initials: N
authors.lastname: Higuchi
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001921:Brain / Q000201:enzymology; D002417:Cattle; D005417:Flavobacterium / Q000201:enzymology; D007202:Indicators and Reagents; D007700:Kinetics; D008969:Molecular Sequence Data; D011392:Proline / Q000031:analogs & derivatives* / Q000494:pharmacology; D000085822:Prolyl Oligopeptidases; D011480:Protease Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology; D011619:Psychotropic Drugs / Q000138:chemical synthesis*; D012697:Serine Endopeptidases; D015842:Serine Proteinase Inhibitors; D013329:Structure-Activity Relationship
chemical_list: D007202:Indicators and Reagents; D011480:Protease Inhibitors; D011619:Psychotropic Drugs; D015842:Serine Proteinase Inhibitors; D011392:Proline; D012697:Serine Endopeptidases; D000085822:Prolyl Oligopeptidases; C046026:prolinal