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Cyclic insulin-regulated aminopeptidase (IRAP)/AT(4) receptor ligands
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry.
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2006 (English)In: Journal of Peptide Science, ISSN 1075-2617, E-ISSN 1099-1387, Vol. 12, no 11, 705-713 p.Article in journal (Refereed) Published
Abstract [en]

The angiotensin IV receptor (AT(4) receptor) is the insulin-regulated aminopeptidase enzyme (IRAP, EC This membrane-spanning enzyme belongs to the M1 family of zinc-dependent metallo-peptidases. It has been proposed that AT4 receptor ligands exert their physiological effects by binding to the active site of IRAP and thereby inhibiting the catalytic activity of the enzyme. The biological activity of a large series of linear angiotensin IV analogs was previously disclosed. Herein, the synthesis and biological evaluation of a series of angiotensin IV analogs, encompassing macrocyclic ring systems of different sizes, are presented. It is demonstrated that disulfide cyclizations of angiotensin IV can deliver ligands with high IRAP/AT4 receptor affinity. One ligand, with an 11-membered ring system (4), inhibited human IRAP and aminopeptidase N (AP-N) activity with similar potency as angiotensin IV but was considerably more stable than angiotensin IV toward enzymatic degradation. The compound provides a promising starting point for further optimization toward more drug-like derivatives. The cyclic constrained analogs allowed us to propose a tentative bioactive conformation of angiotensin IV and it seems that the peptide adopts an inverse gamma-turn at the C-terminal.

Place, publisher, year, edition, pages
2006. Vol. 12, no 11, 705-713 p.
Keyword [en]
angiotensin IV, insulin-regulated aminopeptidase, IRAP, cystinyl aminopeptidase, aminopeptidase N, disulfide cyclization, structure -activity relationship, peptide synthesis, bioactive conformation
National Category
Pharmaceutical Sciences
URN: urn:nbn:se:uu:diva-24521DOI: 10.1002/psc.782ISI: 000241971600004PubMedID: 16967438OAI: oai:DiVA.org:uu-24521DiVA: diva2:52295
Available from: 2007-02-06 Created: 2007-02-06 Last updated: 2012-10-03

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Hallberg, Mathias
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Department of Medicinal ChemistryDepartment of Pharmaceutical Biosciences
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