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Synthesis of a new class of druglike angiotensin II C-terminal mimics with affinity for the AT2 receptor
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences, Biological Research on Drug Dependence.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
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2007 (English)In: Journal of Medicinal Chemistry, ISSN 0022-2623, E-ISSN 1520-4804, Vol. 50, no 7, 1711-1715 p.Article in journal (Refereed) Published
Abstract [en]

Four tripeptides corresponding to the C-terminal region of angiotensin II were synthesized. One of these peptides (Ac-His-Pro-Ile) showed moderate binding affinity for the AT2 receptor. Two aromatic histidine-related scaffolds were synthesized and introduced in the tripeptides to give eight new peptidomimetic structures. Three of the new peptide-derived druglike molecules exhibited selective, nanomolar affinity for the AT2 receptor. These ligands may become lead compounds in the future development of novel classes of selective AT2 receptor agonists.

Place, publisher, year, edition, pages
2007. Vol. 50, no 7, 1711-1715 p.
National Category
Pharmaceutical Sciences
Identifiers
URN: urn:nbn:se:uu:diva-95771DOI: 10.1021/jm0613469ISI: 000245259000033PubMedID: 17358051OAI: oai:DiVA.org:uu-95771DiVA: diva2:170107
Available from: 2007-04-17 Created: 2007-04-17 Last updated: 2011-02-09Bibliographically approved
In thesis
1. Computational Modeling of the AT2 Receptor and AT2 Receptor Ligands: Investigating Ligand Binding, Structure–Activity Relationships, and Receptor-Bound Models
Open this publication in new window or tab >>Computational Modeling of the AT2 Receptor and AT2 Receptor Ligands: Investigating Ligand Binding, Structure–Activity Relationships, and Receptor-Bound Models
2007 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Rational conversion of biologically active peptides to nonpeptide compounds with retained activity is an appealing approach in drug development. One important objective of the work presented in this thesis was to use computational modeling to aid in such a conversion of the peptide angiotensin II (Ang II, Asp-Arg-Val-Tyr-Ile-His-Pro-Phe). An equally important objective was to gain an understanding of the requirements for ligand binding to the Ang II receptors, with a focus on interactions with the AT2 receptor.

The bioactive conformation of a peptide can provide important guidance in peptidomimetic design. By designing and introducing well-defined secondary structure mimetics into Ang II the bioactive conformation can be addressed. In this work, both γ- and β-turn mimetic scaffolds have been designed and characterized for incorporation into Ang II. Using conformational analysis and the pharmacophore recognition method DISCO, a model was derived of the binding mode of the pseudopeptide Ang II analogues. This model indicated that the positioning of the Arg side chain was important for AT2 receptor binding, which was also supported when the structure–activity relationship of Ang II was investigated by performing a glycine scan.

To further examine ligand binding, a 3D model of the AT2 receptor was constructed employing homology modeling. Using this receptor model in a docking study of the ligands, binding modes were identified that were in agreement with data from point-mutation studies of the AT2 receptor.

By investigating truncated Ang II analogues, small pseudopeptides were developed that were structurally similar to nonpeptide AT2 receptor ligands. For further guidance in ligand design of nonpeptide compounds, three-dimensional quantitative structure–activity relationship models for AT1 and AT2 receptor affinity as well as selectivity were derived.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2007. 78 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Pharmacy, ISSN 1651-6192 ; 54
Keyword
Pharmaceutical chemistry, Angiotensin II, AT1, AT2, SAR, bioactive conformation, turn mimetic, peptidomimetic, DISCO, homology model, 3D-QSAR, CoMFA, Farmaceutisk kemi
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-7823 (URN)978-91-554-6867-5 (ISBN)
Public defence
2007-05-11, B41, BMC, Husargatan 3, Uppsala, 13:15
Opponent
Supervisors
Available from: 2007-04-17 Created: 2007-04-17 Last updated: 2012-05-16Bibliographically approved
2. 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)
Opponent
Supervisors
Available from: 2006-01-13 Created: 2006-01-13 Last updated: 2013-09-04Bibliographically approved

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