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Design, Synthesis, and Biological Evaluation of the First Selective Nonpeptide AT2 Receptor Agonist
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry. (OrgFarmKemi)
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry. (OrgFarmKemi)
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2004 (English)In: Journal of Medicinal Chemistry, ISSN 0022-2623, E-ISSN 1520-4804, Vol. 47, no 24, 5995-6008 p.Article in journal (Refereed) Published
Abstract [en]

The first druglike selective angiotensin II AT(2) receptor agonist (21) with a K(i) value of 0.4 nM for the AT(2) receptor and a K(i) > 10 microM for the AT(1) receptor is reported. Compound 21, with a bioavailability of 20-30% after oral administration and a half-life estimated to 4 h in rat, induces outgrowth of neurite cells, stimulates p42/p44(mapk), enhances in vivo duodenal alkaline secretion in Sprague-Dawley rats, and lowers the mean arterial blood pressure in anesthetized, spontaneously hypertensive rats. Thus, the peptidomimetic 21 exerts a similar biological response as the endogenous peptide angiotensin II after selective activation of the AT(2) receptor. Compound 21, derived from the prototype nonselective AT(1)/AT(2) receptor agonist L-162,313 will serve as a valuable research tool, enabling studies of the function of the AT(2) receptor in more detail.

Place, publisher, year, edition, pages
2004. Vol. 47, no 24, 5995-6008 p.
Keyword [en]
Administration; Oral, Animals, Antihypertensive Agents/chemical synthesis/chemistry/pharmacology, Bicarbonates/metabolism, Biological Availability, Cell Line, Drug Design, Enzyme Activation, Female, Half-Life, In Vitro, Intestinal Mucosa/metabolism, Liver/metabolism, Male, Mitogen-Activated Protein Kinases/metabolism, Molecular Mimicry, Neurites/drug effects/physiology, Peptides/chemistry, Radioligand Assay, Rats, Rats; Inbred SHR, Rats; Sprague-Dawley, Receptor; Angiotensin; Type 2/*agonists/metabolism, Research Support; Non-U.S. Gov't, Sulfonamides/*chemical synthesis/chemistry/pharmacology, Swine, Thiophenes/*chemical synthesis/chemistry/pharmacology, Uterus/metabolism
National Category
Medical and Health Sciences
URN: urn:nbn:se:uu:diva-97463DOI: 10.1021/jm049715tPubMedID: 15537354OAI: oai:DiVA.org:uu-97463DiVA: diva2:172423
Available from: 2008-09-05 Created: 2008-09-05 Last updated: 2013-09-04Bibliographically approved
In thesis
1. Design, Synthesis and Biological Evaluation of Selective Nonpeptide AT2 Receptor Agonists and Antagonists
Open this publication in new window or tab >>Design, Synthesis and Biological Evaluation of Selective Nonpeptide AT2 Receptor Agonists and Antagonists
2008 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

The G protein-coupled receptors (GPCRs) are important targets in drug discovery. In several cases, the endogenous ligands that activate the GPCRs of pharmaceutical interest are peptides. Unfortunately, peptides are in general not suitable as drugs, since the peptide structure is associated with several disadvantages, such as low oral bioavailability, rapid degradation and low receptor subtype selectivity. Thus, there is a strong need for drug-like nonpeptide ligands to peptide-activated GPCRs. However, to discover nonpeptide ligands that mimic the effect of the endogenous peptide, i.e. peptidomimetics, is a tremendous challenge. In fact, morphine and the related opioids were the only known examples of peptidomimetics before 1995 and these ligands were known long before the native endogenous peptide ligands were discovered.

The main objective of the work described in this thesis was to design, synthesize and biologically evaluate selective nonpeptide agonists to the peptide-activated GPCR AT2. The AT2 receptor belongs to the renin–angiotensin system, where the octapeptide angiotensin II (Ang II) is the major effector peptide. Ang II mediates its effects through the two GPCRs AT1 and AT2. The AT1 receptor is already an established target in the treatment of hypertension. The physiological role of the AT2 receptor, which is up-regulated in certain pathological conditions, is not fully understood but it seems to include positive effects such as vasodilatation, tissue repair, tissue regeneration and neuronal differentiation.

In the current investigation we started from the nonpeptide and nonselective (AT1/ AT2) compound L-162,313. This ligand is a known AT1 receptor agonist but its effect on the AT2 receptor was unknown at the start of this project. We were able to show that it acts as an agonist also at the AT2 receptor. Furthermore, stepwise synthetic modifications of L-162,313 led to the identification of the first selective nonpeptide AT2 receptor agonist. Following the discovery of this compound several selective nonpeptide AT2 receptor agonists were identified. It was also revealed that a minor structural alteration of one of these compounds interconverted the functional activity from agonism to antagonism. The structural requirement for agonism vs antagonism was therefore studied. The functionality switch was suggested, at least partly, to be due to the spatial relationship between the methyleneimidazole group and the isobutyl side chain of the compounds. To further investigate the bioactive conformation(s) of this series of compounds enantiomerically pure analogues with conformationally constrained isobutyl chains were prepared. This study revealed that the direction of the isobutyl side chain determine whether the compounds act as agonists or antagonists at the AT2 receptor. Further investigations are required to fully elucidate the bioactive conformation(s) of these nonpeptide AT2 receptor agonists.

We believe that the selective nonpeptide AT2 receptor agonists and antagonists identified in this thesis will serve as important research tools in the continuing investigation of the physiological role of the AT2 receptor. We also believe that these drug-like compounds might provide potential leads in drug discovery processes.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2008. 96 p.
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Pharmacy, ISSN 1651-6192 ; 78
AT2 receptor agonist, AT2 receptor antagonist, Ang II peptidomimetics
urn:nbn:se:uu:diva-9213 (URN)978-91-554-7263-4 (ISBN)
Public defence
2008-09-26, Room B41, BMC, Husargatan 3, Uppsala, 09:15
Available from: 2008-09-05 Created: 2008-09-05Bibliographically approved

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Wallinder, Charlotta
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