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Proceedings of the 31 st European Peptide SymposiumMichal Lebl, Morten Meldal, Knud J. Jensen, Thomas Hoeg-Jensen (Editors)European Peptide Society, 20101) COOH 2)COOH3) COOH 4)HHHH HH5) 6)COOH7)COOH8)OHOHOBradykinin Analogues Acylated on Their N-TerminusMałgorzata Śleszyńska 1 , Dariusz Sobolewski 1 , Tomasz H. Wierzba 2 ,Jiřina Slaninová 3 , and Adam Prahl 11 Department of Chemistry, University of Gdańsk, 80-952, Gdańsk, Poland; 2 Department ofPhysiology, Medical Uniwersity of Gdańsk, 80-211, Gdańsk, Poland; 3 Institute ofOrganic Chemistry and Biochemistry, Academy of Sciences of the Czech Republic,Prague, Czech RepublicIntroductionTwo receptors, B 1 and B 2 , mediate biological activities of BK. These receptors belong to aG-protein-coupled family and their activation stimulates smooth muscle cells, sensorynerve endings, causes vasodilation and microvascular leakage and modulates the responseof immunocompetent cells. There is also considerable evidence that BK contributes to theinflammatory responses [1,2]. Moreover, after injection to the skin, BK produces all of thebasic signs of inflammation. Due to its ability to lower blood pressure, BK has beenimplicated in the pathogenesis of several shock syndromes. The classical B 2 receptors areof high affinity and they seem to require the full bradykinin sequence for effectiveactivation. Accumulated evidence indicates that most of the clinically relevant effects ofbradykinin are functions of B 2 receptors and this is the reason why research on theirantagonists is a topic of great interest.Our previous studies suggested that acylation of the N-terminus of several known B 2antagonists with various kinds of bulky acyl groups consistently improved their antagonisticpotency in rat blood pressure assay. On the other hand, our earlier observations also seemed tosuggest that the effects of acylation on the contractility of isolated rat uterus dependedsubstantially on the chemical character of the acyl group, as we observed that thismodification might either change the range of antagonism or even transform it into agonism.In some recent work we placed two of the previously used groups (9-acridinecarboxylicacid and 9-anthracenecarboxylic acid) in the N-terminus of the BK molecule [3].Proposed modification transformed activity of analogues from agonistic to weakantagonistic in the rat blood pressure test and depressed its agonistic activity in theinteraction with rat uterine receptors. It should be pointed out that these were the firstreported B 2 blockers without any changes in main peptide chain.Results and DiscussionIn the current work we present some pharmacological properties of ten new analogues ofbradykinin modified in the N-terminal part of the molecule (Arg-Pro-Pro-Gly-Phe-Ser-Pro-Phe-Arg) with a variety of acyl substituents. Of the many acylating agents, testedOCH 3OOHOH10)HO9)HONH 2COOHCOOHCOOHH 2N CH 2 (CH 2) 9 CH 2 COOHFig. 1. Structures of acids used.previously on B 2 receptor antagonists, thefollowing residues were used: 1-adamantaneaceticacid (Aaa, 1), 1-adamantane-carboxylicacid (Aca, 2), 4-tert-butylbenzoic acid (t-Bba, 4),4-aminobenzoic acid (Aba, 3), 12-aminododecanoicacid (Adc, 10), succinic acid (Sua, 8), 4-hydroxybenzoic acid (6), 4-hydroxy-3-methoxybenzoicacid (5), 3-(4-hydroxyphe-nyl)propionicacid (9) and 6-hydroxy-2-naphthoic acid (7)(Figure 1). All the peptides were obtained by thesolid-phase method on a Symphony MultiplePeptide Synthesizer (Protein Technologies Inc.,U.S.A.) using the Fmoc-strategy and startingfrom Fmoc-Arg(Pbf)-Wang resin (capacity 0.4mmol/g, 25 μmol scale). The crude peptides weredesalted on a Sephadex G-15 column, andpurified by RP-HPLC. The purity of the peptides was checked using analytical HPLC.MALDI TOF mass spectrometry (molecular ion) was used to confirm the identity of thepure products. Biological activity of the compounds was assessed in the in vitro rat uterustest [4] and the in vivo rat blood pressure test [5]. Pharmacological data of analogues I-X320