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Design and Synthesis of Novel AT2 Receptor Ligands: From Peptides to Drug-Like Molecules
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry.
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. , p. 73
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Pharmacy, ISSN 1651-6192 ; 26
Keywords [en]
Pharmaceutical chemistry, angiotensin II, AT1, AT2, AT2 receptor agonist, peptidomimetics, γ-turn mimetics, carbonylation, microwave, molybdenum hexacarbonyl
Keywords [sv]
Farmaceutisk kemi
National Category
Medicinal Chemistry
Identifiers
URN: urn:nbn:se:uu:diva-6269ISBN: 91-554-6438-6 (print)OAI: oai:DiVA.org:uu-6269DiVA, id: diva2:167572
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: 2018-01-13Bibliographically approved
List of papers
1. Rapid palladium-catalyzed synthesis of esters from aryl halides utilizing Mo(CO)6 as a solid carbon monoxide source
Open this publication in new window or tab >>Rapid palladium-catalyzed synthesis of esters from aryl halides utilizing Mo(CO)6 as a solid carbon monoxide source
2003 (English)In: Journal of Combinatorial Chemistry, Vol. 5, no 4, p. 350-352Article in journal (Refereed) Published
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-93926 (URN)
Available from: 2006-01-13 Created: 2006-01-13 Last updated: 2013-07-04Bibliographically approved
2. Angiotensin II Pseudopeptides Containing 1,3,5-Trisubstituted Benzene Scaffolds with High AT2 Receptor Affinity
Open this publication in new window or tab >>Angiotensin II Pseudopeptides Containing 1,3,5-Trisubstituted Benzene Scaffolds with High AT2 Receptor Affinity
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2005 (English)In: Journal of Medicinal Chemistry, ISSN 0022-2623, E-ISSN 1520-4804, Vol. 48, no 21, p. 6620-6631Article in journal (Refereed) Published
Abstract [en]

Two 1,3,5-trisubstituted aromatic scaffolds intended to serve as γ-turn mimetics have been synthesized and incorporated in five pseudopeptide analogues of angiotensin II (Asp-Arg-Val-Tyr-Ile-His-Pro-Phe), replacing Val-Tyr-Ile, Val-Tyr, or Tyr-Ile. All the tested compounds exhibited nanomolar affinity for the AT2 receptor with the best compound (3) having a Ki of 1.85 nM. Four pseudopeptides were AT2 selective, while one (5) also exhibited good affinity for the AT1 receptor (Ki = 30.3 nM). This pseudopeptide exerted full agonistic activity in an AT2 receptor induced neurite outgrowth assay but displayed no agonistic effect in an AT1 receptor functional assay. Molecular modeling, using the program DISCOtech, showed that the high-affinity ligands could interact similarly with the AT2 receptor as other ligands with high affinity for this receptor. A tentative agonist model is proposed for AT2 receptor activation by angiotensin II analogues. We conclude that the 1,3,5-trisubstituted benzene rings can be conveniently prepared and are suitable as γ-turn mimics.

National Category
Natural Sciences
Identifiers
urn:nbn:se:uu:diva-95768 (URN)10.1021/jm050280z (DOI)
Available from: 2007-04-17 Created: 2007-04-17 Last updated: 2017-12-14Bibliographically approved
3. Short pseudopeptides containing turn scaffolds with high AT(2) receptor affinity
Open this publication in new window or tab >>Short pseudopeptides containing turn scaffolds with high AT(2) receptor affinity
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2006 (English)In: Bioorganic & Medicinal Chemistry, ISSN 0968-0896, E-ISSN 1464-3391, Vol. 14, no 17, p. 5963-5972Article 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.

Keywords
angiotensin II, AT1 receptor, AT2 receptor, AT2 receptor agonist, pseudopeptides, turn scaffolds
National Category
Pharmaceutical Sciences
Identifiers
urn:nbn:se:uu:diva-93928 (URN)10.1016/j.bmc.2006.05.019 (DOI)000239947500016 ()16753301 (PubMedID)
Available from: 2006-01-13 Created: 2006-01-13 Last updated: 2018-01-13Bibliographically approved
4. Synthesis of a new class of druglike angiotensin II C-terminal mimics with affinity for the AT2 receptor
Open this publication in new window or tab >>Synthesis of a new class of druglike angiotensin II C-terminal mimics with affinity for the AT2 receptor
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2007 (English)In: Journal of Medicinal Chemistry, ISSN 0022-2623, E-ISSN 1520-4804, Vol. 50, no 7, p. 1711-1715Article 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.

National Category
Pharmaceutical Sciences
Identifiers
urn:nbn:se:uu:diva-95771 (URN)10.1021/jm0613469 (DOI)000245259000033 ()17358051 (PubMedID)
Available from: 2007-04-17 Created: 2007-04-17 Last updated: 2018-01-13Bibliographically approved

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