<p>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 AT<sub>1</sub> and AT<sub>2</sub> receptors were the subject of this study.</p><p>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 Tyr<sup>4</sup> when interacting with its AT<sub>1</sub> receptor. Therefore, two <i>γ</i>- and one <i>β</i>-turn mimetic scaffolds based on the benzodiazepine structure were synthesized and decorated with side chains. The scaffolds replaced the turn region around Tyr<sup>4</sup>. Most of the pseudopeptides obtained after incorporation into Ang II exhibited high AT<sub>2</sub>/AT<sub>1</sub> selectivity and nanomolar affinity to the AT<sub>2</sub> receptor. One pseudopeptide encompassing a <i>β</i>-turn mimetic also displayed AT<sub>1</sub> receptor affinity.</p><p>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 AT<sub>2</sub> receptor affinity. Conformational evaluation of the pseudopeptides revealed that in all the compounds with AT<sub>2</sub> 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 AT<sub>2</sub> receptor than when binding to the AT<sub>1</sub> receptor.</p><p>Furthermore, in a Gly scan of Ang II only replacement of the arginine residue reduced the affinity for the AT<sub>2</sub> receptor considerably. Some N-terminal modified Ang II analogues were also synthesized and it was concluded that truncated Ang II analogues interact with the AT<sub>2</sub> receptor differently than Ang II.</p><p>Three of the synthesized pseudopeptides were evaluated in AT<sub>2</sub> receptor functional assays and were found to act as agonists.</p>
| Identifer | oai:union.ndltd.org:UPSALLA/oai:DiVA.org:uu-4642 |
| Date | January 2004 |
| Creators | Rosenström, Ulrika |
| 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 | Comprehensive Summaries of Uppsala Dissertations from the Faculty of Pharmacy, 0282-7484 ; 316 |
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