<p>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. </p><p>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 AT<sub>2</sub>. The AT<sub>2</sub> 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 AT<sub>1</sub> and AT<sub>2</sub>. The AT<sub>1</sub> receptor is already an established target in the treatment of hypertension. The physiological role of the AT<sub>2</sub> 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. </p><p>In the current investigation we started from the nonpeptide and nonselective (AT<sub>1</sub>/ AT<sub>2</sub>) compound L-162,313. This ligand is a known AT<sub>1</sub> receptor agonist but its effect on the AT<sub>2</sub> receptor was unknown at the start of this project. We were able to show that it acts as an agonist also at the AT<sub>2</sub> receptor. Furthermore, stepwise synthetic modifications of L-162,313 led to the identification of the first selective nonpeptide AT<sub>2</sub> receptor agonist. Following the discovery of this compound several selective nonpeptide AT<sub>2</sub> 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 AT<sub>2</sub> receptor. Further investigations are required to fully elucidate the bioactive conformation(s) of these nonpeptide AT<sub>2</sub> receptor agonists.</p><p>We believe that the selective nonpeptide AT<sub>2</sub> receptor agonists and antagonists identified in this thesis will serve as important research tools in the continuing investigation of the physiological role of the AT<sub>2</sub> receptor. We also believe that these drug-like compounds might provide potential leads in drug discovery processes.</p>
| Identifer | oai:union.ndltd.org:UPSALLA/oai:DiVA.org:uu-9213 |
| Date | January 2008 |
| Creators | Wallinder, Charlotta |
| Publisher | Uppsala University, Department of Medicinal Chemistry, Uppsala : Acta Universitatis Upsaliensis |
| Source Sets | DiVA Archive at Upsalla University |
| Language | English |
| Detected Language | English |
| Type | Doctoral thesis, comprehensive summary, text |
| Relation | Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Pharmacy, 1651-6192 ; 78 |
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