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New selective AT2 receptor ligands encompassing a γ-turn mimetic replacing the amino acid residues 4-5 of angiotensin II act as agonists
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.
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2005 (English)In: Journal of Medicinal Chemistry, ISSN 0022-2623, E-ISSN 1520-4804, Vol. 48, no 12, 4009-4024 p.Article in journal (Refereed) Published
Abstract [en]

New benzodiazepine-based γ-turn mimetics with one or two amino acid side chains were synthesized. The γ-turn mimetics were incorporated into angiotensin II (Ang II) replacing the Val3-Tyr4-Ile5 or Tyr4-Ile5 peptide segments. All of the resulting pseudopeptides displayed high AT2/AT1 receptor selectivity and exhibited AT2 receptor affinity in the low nanomolar range. Molecular modeling was used to investigate whether the compounds binding to the AT2 receptor could position important structural elements in common areas. A previously described benzodiazepine-based γ-turn mimetic with high affinity for the AT2 receptor was also included in the modeling. It was found that the molecules, although being structurally quite different, could adopt the same binding mode/interaction pattern in agreement with the model hypothesis. The pseudopeptides selected for agonist studies were shown to act as AT2 receptor agonists being able to induce outgrowth of neurite cells, stimulate p42/p44mapk, and suppress proliferation of PC12 cells.

Place, publisher, year, edition, pages
2005. Vol. 48, no 12, 4009-4024 p.
National Category
Medical and Health Sciences
Identifiers
URN: urn:nbn:se:uu:diva-95767DOI: 10.1021/jm0491492OAI: oai:DiVA.org:uu-95767DiVA: diva2:170103
Available from: 2007-04-17 Created: 2007-04-17 Last updated: 2017-12-14Bibliographically 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 AT2 Receptor Selective Angiotensin II Analogues Encompassing β- and γ-Turn Mimetics
Open this publication in new window or tab >>Design and Synthesis of AT2 Receptor Selective Angiotensin II Analogues Encompassing β- and γ-Turn Mimetics
2004 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Important information on the bioactive conformation of biologically active peptides may be obtained by studies of rigid peptides or well-defined secondary structure mimetics incorporated into pseudopeptides. The structural requirements for the interaction of angiotensin II (Ang II, Asp-Arg-Val-Tyr-Ile-His-Pro-Phe) with its AT1 and AT2 receptors were the subject of this study.

The main objectives of this work were to synthesize secondary structure mimetics and incorporate these into Ang II. Ang II has been suggested to adopt a turn conformation around Tyr4 when interacting with its AT1 receptor. Therefore, two γ- and one β-turn mimetic scaffolds based on the benzodiazepine structure were synthesized and decorated with side chains. The scaffolds replaced the turn region around Tyr4. Most of the pseudopeptides obtained after incorporation into Ang II exhibited high AT2/AT1 selectivity and nanomolar affinity to the AT2 receptor. One pseudopeptide encompassing a β-turn mimetic also displayed AT1 receptor affinity.

We hypothesized that the position of the guanidino group of the arginine residue and the N-terminal end, in relation to the tyrosine side chain, was critical for AT2 receptor affinity. Conformational evaluation of the pseudopeptides revealed that in all the compounds with AT2 receptor affinity the arginine side chain and the N-terminal end could reach common regions, not accessible to the inactive compound. It is proposed that Ang II has a more extended bioactive conformation when binding to the AT2 receptor than when binding to the AT1 receptor.

Furthermore, in a Gly scan of Ang II only replacement of the arginine residue reduced the affinity for the AT2 receptor considerably. Some N-terminal modified Ang II analogues were also synthesized and it was concluded that truncated Ang II analogues interact with the AT2 receptor differently than Ang II.

Three of the synthesized pseudopeptides were evaluated in AT2 receptor functional assays and were found to act as agonists.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2004. 81 p.
Series
Comprehensive Summaries of Uppsala Dissertations from the Faculty of Pharmacy, ISSN 0282-7484 ; 316
Keyword
Pharmaceutical chemistry, Angiotensin II, AT2, AT1, Benzodiazepine, Peptidomimetics, γ-turn, β-turn, Farmaceutisk kemi
National Category
Medicinal Chemistry
Identifiers
urn:nbn:se:uu:diva-4642 (URN)91-554-6078-X (ISBN)
Public defence
2004-12-03, B42, BMC, Husargatan 3, Uppsala, 13:15
Opponent
Supervisors
Available from: 2004-11-10 Created: 2004-11-10 Last updated: 2012-05-16Bibliographically approved

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Rosenström, UlrikaSköld, ChristianLindeberg, GunnarNyberg, FredKarlén, AndersHallberg, Anders

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