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Short pseudopeptides containing turn scaffolds with high AT(2) receptor affinity
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.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry.
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2006 (English)In: Bioorganic & Medicinal Chemistry, ISSN 0968-0896, E-ISSN 1464-3391, Vol. 14, no 17, 5963-5972 p.Article in journal (Refereed) Published
Abstract [en]

Two pentapeptides, Ac-Tyr-Ile-His-Pro-Phe/Ile, were synthesized and shown to have angiotensin II AT(2) receptor affinity and agonistic activity. Based on these peptides, a new series of 13 pseudopeptides was synthesized via introduction of five different turn scaffolds replacing the Tyr-Ile amino acid residues. Pharmacological evaluation disclosed subnanomolar affinities for some of these compounds at the AT(2) receptor. Substitution of Phe by Ile in this series of ligands enhanced the AT(2) receptor affinity of all compounds. These results suggest that the C-terminal amino acid residues can be elaborated on to enhance the AT(2) receptor affinity in truncated Ang II analogues.

Place, publisher, year, edition, pages
2006. Vol. 14, no 17, 5963-5972 p.
Keyword [en]
angiotensin II, AT1 receptor, AT2 receptor, AT2 receptor agonist, pseudopeptides, turn scaffolds
National Category
Pharmaceutical Sciences
Identifiers
URN: urn:nbn:se:uu:diva-93928DOI: 10.1016/j.bmc.2006.05.019ISI: 000239947500016PubMedID: 16753301OAI: oai:DiVA.org:uu-93928DiVA: diva2:167570
Available from: 2006-01-13 Created: 2006-01-13 Last updated: 2017-12-14Bibliographically approved
In thesis
1. Design and Synthesis of Novel AT2 Receptor Ligands: From Peptides to Drug-Like Molecules
Open this publication in new window or tab >>Design and Synthesis of Novel AT2 Receptor Ligands: From Peptides to Drug-Like Molecules
2006 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Many peptide receptors are of pharmaceutical interest and there is thus a need for new ligands for such receptors. Unfortunately, peptides are not suitable as orally administrated drugs since they are associated with poor absorption, rapid metabolism and low sub-receptor selectivity. One approach that should allow identification of more drug-like ligands is to use the structural information of the endogenous ligand to develop peptidomimetic compounds.

The main objective of the work described in this thesis was to convert angiotensin II (Ang II, Asp-Arg-Val-Tyr-Ile-His-Pro-Phe) to small drug-like compounds with retained bioactivity at the AT2 receptor. The study was performed step-wise via incorporation of well-defined secondary structure mimetics and repeated truncation of the peptide. Five scaffolds, comprising a benzene ring as a central element, suitable as a γ-turn or dipeptide mimetics were designed and synthesized. In order to decorate the scaffolds, a method of microwave-assisted alkoxycarbonylation was developed. After incorporation of the scaffolds into Ang II-related peptides or peptide fragments, the affinities for both the AT1 and the AT2 receptor were determined.

In the first series of ligands, two tyrosine-related scaffolds were introduced as γ-turn mimetics in Ang II. All five pseudopeptides exhibited good affinities for the AT2 receptor. One compound was chosen for functional studies and was shown to act as an AT2 receptor agonist. After truncation of Ang II it was shown that C-terminal pentapeptide analogs were AT2 receptor selective agonists. A series of pseudopeptides comprising tyrosine-related scaffolds, derived from the pentapeptides, displayed high AT2 receptor affinities. Two compounds had agonistic effect at the AT2 receptor.

This study revealed that the N-terminal part was of less importance while a C-terminal Ile residue was a key element for enhanced AT2 receptor affinity. In the final set of compounds, the peptide was truncated to tripeptide C-terminal fragments. After replacing His-Pro by a histidine-related scaffold small drug-like peptidomimetic compounds with nanomolar affinity for the AT2 receptor were identified.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2006. 73 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Pharmacy, ISSN 1651-6192 ; 26
Keyword
Pharmaceutical chemistry, angiotensin II, AT1, AT2, AT2 receptor agonist, peptidomimetics, γ-turn mimetics, carbonylation, microwave, molybdenum hexacarbonyl, Farmaceutisk kemi
National Category
Medicinal Chemistry
Identifiers
urn:nbn:se:uu:diva-6269 (URN)91-554-6438-6 (ISBN)
Public defence
2006-02-03, B42, Bio Medical Centre (BMC), Husargatan 3, Uppsala, 13:15 (English)
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Available from: 2006-01-13 Created: 2006-01-13 Last updated: 2013-09-04Bibliographically approved

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Rosenström, UlrikaWallinder, CharlottaLindeberg, GunnarBotros, MiladNyberg, FredKarlén, AndersHallberg, Anders

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