title: Small potent ligands to the insulin-regulated aminopeptidase (IRAP)/AT(4) receptor.
abstract: Angiotensin IV analogs encompassing aromatic scaffolds replacing parts of the backbone of angiotensin IV have been synthesized and evaluated in biological assays. Several of the ligands displayed high affinities to the insulin-regulated aminopeptidase (IRAP)/AT(4) receptor. Displacement of the C-terminal of angiotensin IV with an o-substituted aryl acetic acid derivative delivered the ligand 4, which exhibited the highest binding affinity (K(i) = 1.9 nM). The high affinity of this ligand provides support to the hypothesis that angiotensin IV adopts a gamma-turn in the C-terminal of its bioactive conformation. Ligand (4) inhibits both human IRAP and aminopeptidase N-activity and induces proliferation of adult neural stem cells at low concentrations. Furthermore, ligand 4 is degraded considerably more slowly in membrane preparations than angiotensin IV. Hence, it might constitute a suitable research tool for biological studies of the (IRAP)/AT(4) receptor.
authors.affiliation: Department of Medicinal Chemistry, Uppsala University, Box 574, SE-751 23 Uppsala, Sweden.
authors.forename: Andreas
authors.initials: A
authors.lastname: Axén
authors.forename: Hanna
authors.initials: H
authors.lastname: Andersson
authors.forename: Gunnar
authors.initials: G
authors.lastname: Lindeberg
authors.forename: Harriet
authors.initials: H
authors.lastname: Rönnholm
authors.forename: Jarkko
authors.initials: J
authors.lastname: Kortesmaa
authors.forename: Heidi
authors.initials: H
authors.lastname: Demaegdt
authors.forename: Georges
authors.initials: G
authors.lastname: Vauquelin
authors.forename: Anders
authors.initials: A
authors.lastname: Karlén
authors.forename: Mathias
authors.initials: M
authors.lastname: Hallberg
mesh_terms: D000804:Angiotensin II / Q000031:analogs & derivatives / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism; D000818:Animals; D002460:Cell Line; D002462:Cell Membrane / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D006224:Cricetinae; D003412:Cricetulus; D010122:Cystinyl Aminopeptidase / Q000235:genetics / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D015971:Gene Expression Regulation, Enzymologic; D006801:Humans; D008024:Ligands; D051379:Mice; D008958:Models, Molecular; D009474:Neurons / Q000166:cytology / Q000187:drug effects; D009842:Oligopeptides / Q000138:chemical synthesis / Q000378:metabolism* / Q000494:pharmacology; D011485:Protein Binding; D011487:Protein Conformation; D011869:Radioligand Assay; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013234:Stem Cells / Q000166:cytology / Q000187:drug effects; D013329:Structure-Activity Relationship; D013552:Swine; D014162:Transfection
chemical_list: D008024:Ligands; D009842:Oligopeptides; D000804:Angiotensin II; C012877:angiotensin II, des-Asp(1)-des-Arg(2)-Ile(5)-; D010122:Cystinyl Aminopeptidase; C105964:leucyl-cystinyl aminopeptidase